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RNA m6A methylation regulators in endometrial cancer (Review)

  • Authors:
    • Siyi Shen
    • Jialu Guo
    • Nengyuan Lv
    • Qianying Chen
    • Jinyi Tong
  • View Affiliations

  • Published online on: November 1, 2022
  • Article Number: 155
  • Copyright: © Shen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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As one of the three major malignant tumor types of the female reproductive system, endometrial cancer (EC) is the most prevalent gynecologic cancer in developed countries. In recent years, the incidence of EC has increased worldwide, threatening the health and well‑being of women. Recent research has indicated that the expression of multiple N6‑methyladenosine (m6A) regulators is up‑ or downregulated in EC and that abnormalities in m6A methylation and the expression of associated regulators are critical to the pathogenesis and progression of EC. m6A is the most abundant internal modification of mRNA. Several studies have demonstrated a close association between the development and progression of malignant tumors and the epigenetic phenomenon of m6A methylation. In the present study, the current status of research on m6A methylation in EC was reviewed. The mechanisms of methyltransferase, demethylase and m6A binding protein in regulating the development and progression of EC by modifying mRNA were introduced. The related research results will provide novel methods and approaches for the prevention and treatment of EC.

1. Introduction

Endometrial cancer (EC) is the most prevalent gynecologic cancer in developed countries and its incidence rate has rapidly increased in recent years (1). The most common histological subtype is endometrioid adenocarcinoma originating from the endometrial glands. The mainstay of treatment includes total hysterectomy and bilateral salpingo-oophorectomy, followed by adjuvant treatment according to the final histology and stage (2). Although the prognosis of patients with an early diagnosis of EC is favorable, there are fewer choices and shorter median overall survival (OS) for patients with recurrent or metastatic diseases (3).

N6-methyladenosine (m6A) is the most abundant RNA modification in mammalian mRNA and has a crucial role in the occurrence and development of various diseases, particularly malignant tumors (4,5). As a hot topic in epigenetics, m6A modification is essential for regulating various biological processes, such as splicing, translation and stability of mRNA through related regulators, thus affecting the proliferation, invasion, metastasis and self-renewal of tumor cells (6,7). In recent years, the function of m6A in the pathogenesis and progression of diseases has attracted considerable attention, particularly in the prevention and treatment of malignant tumors. It is anticipated that m6A and the associated regulators will emerge as new therapeutic targets and prognostic indicators (8).

Although the exploration of RNA-based therapy is in its infancy, it has already gained widespread acceptance, as methylated RNA molecules have important roles in regulating almost all aspects of cellular biology and may be specifically identified (9), indicating that therapies based on RNA modifications may be a valuable method in the field of cancer treatment. Recent studies reported that the expression of multiple m6A regulators is up- or downregulated in EC and that m6A methylation and related regulators are critical to the pathogenesis and progression of EC. This review discusses the relationship between m6A methylation modification, related regulators and EC in the hope that the related findings will provide novel avenues and approaches for the prevention, early diagnosis and treatment of EC.

2. EC

ECs are a group of epithelial malignancies that occur in the endometrium, with adenocarcinoma originating from the endometrial glands being the most common. It is a major malignancy of the female reproductive tract and the most prevalent gynecological cancer in developed countries. In recent years, its incidence has increased worldwide (2,10,11), threatening the health and well-being of women (12).

EC is usually divided into two histological types, with a significant prognostic difference between them. Type I is estrogen-dependent and may occur under continuous estrogen stimulation in the absence of progesterone antagonism, resulting in abnormal proliferation of endometrial epithelial cells (13). Type I EC is frequently associated with obesity, hypertension, diabetes, anovulatory uterine bleeding and long-term use of single estrogen or tamoxifen. Type I EC is histologically classified as well-differentiated to moderately differentiated tumors, with at least 90% of cases expressing moderate to high levels of the estrogen receptor. Type I tumors are characterized by phosphatase and tensin homolog deletion and mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α, KRAS and β-catenin, as well as microsatellite instability (MSI) (14,15). By contrast, type II EC is not related to hyperestrogenemia or endometrial hyperplasia, frequently occurs in nonobese women and is unrelated to metabolic or endocrine disorders. Histologically, type II tumors are poorly differentiated and are most commonly of plasmacytotic, clear cell or carcinosarcoma subtypes. They are clinically aggressive and are related to a more advanced stage at initial presentation and a higher risk of recurrence (16). Type II tumors are not estrogen-related and are usually distinguished by a genetic alteration in p53, HER2/neu, p16 and E-cadherin (14,15).

Recent studies have indicated that despite the dualistic typing of EC, there are a considerable number of cases that exhibit an intersection of molecular characteristics, and not all cases are completely consistent with the pathological characteristics. Therefore, through genome sequencing analysis, EC may instead be divided into four subtypes according to the molecular characteristics: DNA polymerase epsilon (POLE) ultramutated, MSI, copy-number high (CN high) and CN low (17,18). Molecular typing has a high predictive value for the prognosis of EC (19). It has been indicated that 60% of POLE ultramutated EC cases are high-grade endometrioid lesions with favorable prognostic outcomes, while the prognosis of CN-high is the most unfavorable (20-22).

With the continuous growth of the population, the incidence of EC has increased rapidly in the past decade due to the high prevalence of obesity and metabolic syndrome (23,24). Obesity is more closely associated with the progression of EC than any other type of female-specific cancer. The rate of obesity in the population is increasing and more than half of all EC cases are currently attributable to obesity, which is regarded as an independent risk factor for EC (13). This relationship may be largely explained by the prevalence of a high level of estrogen in obese women. Obesity is also related to a high level of insulin. Higher levels of insulin and estrogen are associated with the risk of EC (25,26). However, the pathogenesis of EC remains to be fully elucidated. Therefore, further research on the mechanisms underlying the development of EC remains crucial for the development of scientifically effective preventative and therapeutic measures.

3. m6A

Relatively recently, m6A has become a topic of intense interest in the field of epigenetics. It is of great significance in the development and progression of a diverse range of diseases, particularly malignant tumors (4,5). m6A refers to a specific methylation modification formed by the catalysis of the sixth nitrogen atom (N) on adenine (A) by methyltransferase. The m6A modification sites are primarily distributed close to the termination codon and the 3′-untranslated region (3′UTR) (27). They are widely found in mRNAs and non-coding RNAs (ncRNAs) (28), having important roles in influencing the biological behavior of RNAs. m6A exists in a variety of RNAs but is most abundant in eukaryotic mRNAs (29,30), adding additional complexity to the RNA world. This modification is dynamic and reversible, and it is catalyzed by three main types of regulator: It may be installed by methyltransferases [methyltransferase-like 3 (METTL3), METTL14, Wilms tumor 1-associated protein (WTAP), vir-like m6A methyltransferase-associated protein (VIRMA, also called KIAA1429), RNA binding motif protein 15/15B (RBM15/15B) and zinc finger CCCH domain-containing protein 13 (ZC3H13)], erased by demethylases [fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5)] and interacts with RNA-binding proteins such as the YT521-B homology (YTH) domain family, heterogeneous nuclear ribonucleoprotein (HNRNP) protein family and insulin-like growth factor 2 mRNA binding proteins (IGF2BP) family to exert their biological effects. By influencing several phases of an mRNA′s life, m6A alterations and associated regulators have critical roles in terms of gene expression (31-33). The regular functions of these regulators are significant and abnormal expression is clearly associated with human cancer (7).

m6A writers

METTL3, METTL14 and WTAP form the m6A methyltransferase core complex, and are also referred to as 'writers'. METTL3 is the catalytic core enzyme of this complex (34). METTL14 is the structural support partner of METTL3 and has a structural role in stabilizing METTL3 and recognizing target RNAs. Together, they form a stable heterodimeric core complex that allows m6A to be deposited on mammalian nuclear RNAs (35,36). WTAP has a crucial role in the localization of METTL3/14 at the nuclear speckles and may interact with this complex to influence this methylation (34,35,37). In addition to the core components, there are several additional regulatory factors involved in the m6A methylation process. For instance, it was discovered that the elements linked to WTAP in mammalian cells include VIRMA (KIAA1429) and HAKAI. VIRMA mediates preferential mRNA methylation in the 3'UTR and close to the termination codon. VIRMA enlists the methyltransferase core complex as its catalytic core member to control region-selective methylation (38). RBM15/15B binds to U-rich sequences preferentially to attract the m6A complex and may encourage the methylation of particular RNAs (39). ZC3H13 is a CCCH zinc finger protein that suppresses the growth of tumors by influencing the Ras-ERK signaling pathway (40). WTAP, VIRMA and HAKAI are anchored in the nucleus by ZC3H13, which regulates m6A methylation and mESC self-renewal (41). The functions of m6A writers are summarized in Table I.

Table I

Functions of m6A 'writers'.

Table I

Functions of m6A 'writers'.

RegulatorEffect on m6A modification(Refs.)
METTL3The catalytic core of methyltransferase(34)
METTL14Forms a heterodimer with METTL3 and catalyze m6A modification(35,36)
WTAPRecruits METTL3 and METTL14 into the nuclear speckles(37)
KIAA1429 (VIRMA)Interacts with WTAP and attaches m6A to the 3' UTR(38)
RBM15/15BRecruits the methyltransferase complex(39)
ZC3H13Promotes the WTAP localization and m6A deposition(41)

[i] m6A, N6-methyladenosine; METTL3, methyltransferase-like 3; WTAP, Wilms tumor 1-associated protein; VIRMA, also called KIAA1429, vir-like m6A methyltransferase-associated protein; RBM15/15B, RNA binding motif protein 15/15B; ZC3H13, zinc finger CCCH domain-containing protein 13.

m6A erasers

To date, FTO and ALKBH5 are the only two m6A demethylases that have been reported (42). These 'erasers' are members of the AlkB dioxygenases family and require oxygen, ferrous ion and α-ketoglutarate to function. FTO, the first m6A demethylase, was identified in 2011 as being effective in removing m6A modifications from RNA, indicating that m6A RNA methylation is reversible (43). FTO is localized in the cytoplasm and nucleus with different substrate preferences at these two sites (44). FTO knockdown may increase the level of m6A in mRNA, whereas FTO overexpression may decrease the level of m6A in mRNA. Recent research has revealed that FTO preferentially mediates pre-mRNA alternative splicing and 3'UTR processing (45). Furthermore, FTO is closely related to weight growth and fat in humans (46).

ALKBH5, the second eraser, was subsequently discovered in 2013. ALKBH5 is localized to nuclear speckles and contributes to the assembly of mRNA processing factors that regulate gene expression by affecting RNA metabolism, pre-mRNA processing, mRNA decay and translation (47,48). ALKBH5 deficiency increases m6A levels, whereas ALKBH5 overexpression decreases m6A levels in mRNA. Aberrant expression of either FTO or ALKBH5 affects m6A levels, which then influence certain biological processes in tumor cells through a complex series of mechanisms. The functions of m6A erasers are listed in Table II.

Table II

Functions of m6A 'erasers'.

Table II

Functions of m6A 'erasers'.

RegulatorsEffect on m6A modification(Refs.)
FTORemoves m6A modification, regulates pre-mRNA alternative splicing and 3' UTR processing(43,45)
ALKBH5Removes m6A modification, regulates RNA metabolism, pre-mRNA processing, mRNA decay and translation(48)

[i] m6A, N6-methyladenosine; FTO, fat mass and obesity-associated protein; ALKBH5, AlkB homolog 5.

m6A readers

The m6A recognition protein regulates the relevant biological behaviors of mRNA and performs corresponding functions by reading m6A methylation. The YTH family may directly identify m6A methylation and its binding leads to changes in the translation and stability of m6A-modified RNAs. Members of the YTH family include YTHDC1-2 and YTHDF1-3 (49).

YTHDF2 may accelerate the degradation of m6A methylated transcripts by directly recruiting the CCR4-NOT deadenylase complex (50,51). In addition, YTHDF2 may prevent FTO from demethylating the 5'UTR, stabilizing the methylation levels in cells (52). YTHDF1 may facilitate the translation efficiency of m6A-modified transcripts, attaches to the m6A sites near the termination codon and improves the translation of target RNAs by cooperating with the translation initiation mechanism (53,54). YTHDF3 cooperates with YTHDF1 to promote RNA translation, while accelerating mRNA degradation by cooperating with YTHDF2, suggesting a cooperative relationship between YTHDF proteins (55,56). YTHDC1 is widely distributed in the nucleus with multiple regulatory functions. YTHDC1 recruits a variety of splicing factors to promote exon inclusion. YTHDC1 may accelerate the nuclear export of m6A-modified mRNAs (57,58). In addition, YTHDC1 may silence the X chromosome (39), and encourage the degradation of certain transcripts (59). YTHDC2 increases the translation efficiency and decreases the abundance of mRNAs by identifying methylated mRNAs (60).

In addition to the YTH structural domain family, the HNRNP family and IGF2BPs serve as m6A readers and may recognize m6A modifications (49). HNRNPA2B1 promotes the processing of primary microRNAs (miRNAs) in an m6A-dependent manner (61). Furthermore, HNRNPC and HNRNPG influence mRNA abundance and splicing by dealing with transcripts with the m6A modification. The RNA secondary structure is impacted by m6A, which makes it easier for transcripts to bind to HNRNPC and HNRNPG and modulate mRNA abundance and splicing (62,63). IGF2BPs are conserved m6A-binding proteins that enhance the stability of their target mRNAs and improve translation efficiency in an m6A-dependent manner, impacting gene regulation and cancer biology (64). The functions of m6A readers are summarized in Table III.

Table III

Functions of m6A 'readers'.

Table III

Functions of m6A 'readers'.

RegulatorsEffect on m6A modification(Refs.)
YTH domain family
 YTHDF1Facilitates the translation of m6A-modified RNA(53)
 YTHDF2Accelerates the degradation of m6A-modified RNA(50)
 YTHDF3Facilitates the translation and degradation of m6A-modified RNA(55,56)
 YTHDC1Regulates the splicing and nuclear export of m6A-modified RNA(57,58)
 YTHDC2Increases the translation efficiency of m6A-modified RNA(60)
HNRNP family
 HNRNPA2B1Promotes the processing of primary miRNA(61)
 HNRNPC and HNRNPGRegulate the abundance and splicing of m6A-modified RNA(62,63)
 IGF2BP1-3Promotes the stability of m6A-modified RNA(64)

[i] m6A, N6-methyladenosine; miRNA, microRNA; YTH, YT521-B homology; YTHDF1, YTH domain family 1; YTHDC1, YTH domain containing 1; HNRNP, heterogeneous nuclear ribonucleoprotein protein; IGF2BP, insulin-like growth factor 2 mRNA binding protein.

4. M6A and EC

According to reports, m6A methylation may mediate post-transcriptional gene expression in EC by regulating functional gene components, particularly gene promoters and the 3'UTR. Further research revealed that highly methylated genes were associated with insulin resistance (IR), while genes with low levels of methylation were notably enriched in extracellular matrix (ECM) tissues and adhesive plaques (65). Therefore, m6A methylation regulates EC progression by focusing on IR and ECM-related genes.

A growing number of studies suggested that m6A regulatory factors are associated with tumors, which may function as oncogenes or tumor suppressor genes to participate in the proliferation, invasion and metastasis of tumor cells (31,66). It was determined that the expression of multiple m6A regulators was up- or downregulated in EC, and that m6A methylation and the expression of the related regulators are critical to the pathogenesis and progression of EC.

In addition, multiple signaling pathways are actively functioning in EC cells, including the MAPK signaling pathway (67,68) and the PI3K/AKT/mTOR signaling pathway (69,70). Research has demonstrated that altering the degree of m6A modification may influence the activity of these signaling pathways and the downstream targets, thereby stimulating the proliferation and invasion of EC cells.

These signaling pathways are involved in numerous physiological and pathological activities. Future studies should thus focus on controlling the activity of these signaling pathways by m6A methylation, as aberrant activation of these pathways may be a significant oncogenic driver of human malignancies. m6A methylation is involved in various biological processes in EC by affecting RNA metabolism and participating in the regulation of RNA expression, translation and decay (71).

The following is a summary of the primary contributions of certain significant m6A regulators in the occurrence and progression of EC (Fig. 1).


The multiple functions, mechanisms and abnormal regulation of METTL3 are associated with a wide range of human tumors. METTL3 is related to a variety of processes in neoplasm progression, including proliferation, aggressiveness, metastasis and drug resistance (72). These outcomes are mediated by stem cell self-renewal, miRNA processing via DGCR8, EMT, apoptosis, the PI3K/AKT pathway and recruitment of eIF3h. Most potential mechanisms involve multiple m6A-dependent signaling pathways, including the PI3K/AKT pathway. METTL3 knockout resulted in a decrease in m6A and thus facilitated the proliferation and invasive ability of tumor cells by activating the PI3K-AKT signaling pathway. METTL3 has different roles in different types of cancers (73). In most cancer tissues, METTL3 is found to be upregulated and carcinogenic, such as lung cancer (74), leukemia (75,76), gastric cancer (77,78) and ovarian cancer (79). By contrast, METTL3 is downregulated in renal cell carcinoma where it acts as a tumor suppressor (80).

Even in the same type of cancer, certain studies have indicated mutually contradictory outcomes. For instance, METTL3 is highly upregulated and associated with unfavorable prognosis in bladder cancer (81,82). On the contrary, other studies revealed that the absence of METTL3 notably stimulated the growth of bladder cancer cells and acted as a tumor suppressor gene in the disease (83). Likewise, Cai et al (84) found that METTL3, as an oncogene, was upregulated in breast cancer. Instead, Wu et al (85) reported that METTL3, as a tumor suppressor, was downregulated in breast cancer.

According to Liu et al (86), loss of function mutations in METTL14 or decreased METTL3 expression may underlie the fact that m6A methylation levels in ~70% of EC were much lower than those in normal endometrial tissues.

The levels of m6A modifications were reduced due to the decreased expression of METTL3 and METTL14, which increased the proliferation and tumorigenicity of EC. According to further research, a reduction in the levels of m6A methylation may boost cell growth by regulating vital enzymes in the AKT signaling pathway. Dysfunctional AKT signaling may lead to cancer, IR, type-2 diabetes, autoimmune diseases and cardiovascular disease, as well as inflammatory and neurological disorders (87,88). The genomic investigation demonstrated that the PI3K/AKT/mTOR signaling pathway, essential for cell metabolism, growth and survival (89), is typically upregulated in EC (69).

In terms of the mechanism, the major AKT Ser473 kinase is the mTORC2. AKT lacking Ser473 phosphorylation is active but the activity is markedly reduced, and phosphorylation of Ser473 stabilizes both Thr308 phosphorylation and the activation state of AKT. The decrease in m6A methylation levels may prevent the decay of the mRNA encoding the mTORC2 complex, which is promoted by YTHDF2, increasing the expression of mTORC2. mTORC2 is a positive regulator of AKT activation and promotes AKT activation by phosphorylating the serine residue at position 473 (69,87,89). On the contrary, m6A methylation reduction reduces PHLPP2 translation promoted by YTHDF1. PHLPP2 is a negative regulatory factor in AKT activation and inhibits the AKT signaling pathway through dephosphorylation of a serine residue at position 473. Since the loss of PHLPP activity leads to the hyperphosphorylation of AKT, it stands to reason that the expression of PHLPP1/2 is reduced or lost in several types of cancer (87).

Therefore, the decrease of m6A mRNA methylation will affect a variety of AKT pathway components and promote the proliferation and tumorigenicity of tumor cells by activating the AKT signaling pathway. The possible mechanism is presented in Fig. 2. On the contrary, the enhanced proliferation brought about by a reduction in m6A methylation was reversed by inhibiting AKT activation.

Figure 2

The levels of m6A modifications were reduced due to the decreased expression of METTL3 and METTL14, which influenced the expression of PHLPP2 and mTORC2 through YTHDF1/2, activating AKT signaling pathway to promote the proliferation and tumorigenicity of tumor cells. PI3K/AKT signaling pathway. AKT is a serine and threonine kinase, which leads to the phosphorylation of serine and threonine residues on target proteins. The growth factor binds to its ligands and activates RTK or GPCR on the cell membrane, so as to activate PI3K. The activated PI3K phosphorylates PIP2 and converts it into PIP3, which increases the level of PIP3, activates PDK1 and activates AKT. i) AKT phosphorylates GSK3, which is an inhibitor of glycogen synthesis, and inhibits its activity, resulting in the activation of GS and increasing glycogen synthesis. ii) AKT inhibits FOXO, which inhibits cell survival and proliferation, thereby increasing cell survival and proliferation. iii) AKT phosphorylates TSC1/2 and inhibits its negative regulation of RHEB, which is an activator of mTORC1, thereby activating mTORC1, resulting in the activation of P70S6K and S6 and promoting protein synthesis. iv) AKT activates ATP citrate lyase and promotes fatty acid synthesis. RTK, receptor tyrosine kinase; GPCR, G protein coupled receptors; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol (3-5)-triphosphate; PDK1, 3-phosphoinositide-dependent kinase 1; GSK3, glycogen synthase kinase 3; FOXO, forkhead box O; TSC1/2, Tuberous Sclerosis Complex 1/2; RHEB, Ras homologue enriched in brain; mTORC1/2, mammalian target of rapamycin complex 1/2; P70S6K, protein 70 S6 kinase; METTL3/14, methyltransferase-like 3/14; YTHDF1/2, YT521-B homology domain family 1/2; PHLPP2, pleckstrin homology domain and leucine-rich repeat protein phosphatase 2; PP2A, protein phosphatase 2 A.

In conclusion, the reduction in m6A methylation may be an oncogenic mechanism in EC and the PI3K/AKT/mTOR pathway may serve as a therapeutic target, suggesting that altering the activity of AKT through an m6A-dependent approach may provide novel approaches for the treatment of malignancies (86).

However, according to Ralser et al (90), the expression levels of METTL3 were increased, which had prognostic significance and was connected to the short OS of patients with EC. They speculated that increased METTL3 expression may result in lower sensitivity to platinum-based chemotherapy, which is the first-line chemotherapeutic regimen for advanced EC.

As the main catalytic enzyme in m6A methylation, METTL3 functions via a complex mechanism and involves a variety of signaling pathways. The exact mechanisms in cancer remain to be completely elucidated and require further research.


WTAP is a nuclear protein that functions as a mammalian splicing factor. An increasing body of knowledge has indicated that WTAP, as an oncogene, is closely related to different malignancies. For instance, WTAP is substantially expressed in high-grade serous ovarian cancer (HGSOC), where it is significantly correlated with lymph node metastasis and a poor prognostic outcome. It is a prognostic marker of HGSOC and regulates the progression of ovarian cancer cells (91). In diffuse large B-cell lymphoma tissues, WTAP is continuously upregulated, promoting cell growth and counteracting apoptosis, and WTAP was able to form a complex with BCL6 via Hsp90 (92). WTAP physically binds to the 3'UTR of CDK2 transcripts and increases the stability of those transcripts and is significantly overexpressed and serves as an oncogene in renal cell cancer (93). WTAP is overexpressed in hepatocellular carcinoma and is closely associated with poor prognosis (94). In gastric cancer, WTAP enhances the stability of HK2 mRNA and promotes the Warburg effect and tumor cell proliferation (95).

However, it remains to be fully elucidated how WTAP may affect EC. Li et al (96) studied the expression levels of WTAP in cancer tissues and para-cancerous tissues from a patient with EC. They observed that WTAP was markedly overexpressed in cancer tissues and associated with poor prognosis. In vivo and in vitro, cell proliferation, invasion and migration were enhanced, and EC apoptosis was reduced, indicating a higher degree of malignancy and unfavorable survival outcomes. Cell invasion and migration may be significantly decreased by WTAP knockdown. When WTAP was knocked out, the expression of CAV-1, a possible WTAP target, was increased and the enrichment of m6A and METTL3 in its 3'UTR was lowered. In addition, CAV1 prevented activation of the NF-κB signaling pathway. In conclusion, WTAP may methylate the 3'UTR of CAV-1 and inhibit its expression in order to activate the NF-κB signaling pathway, thus accelerating the advancement of EC.


Previous reports have indicated that FTO is abundantly expressed in various human malignancies (97) and increases cancer cell metabolism, thus leading to tumorigenesis and chemotherapeutic resistance (98). The elevated expression of FTO in bladder tumor tissue and its association with a poorer prognosis highlights the potential of FTO in the diagnosis and/or prognosis of this disease (99). FTO is involved in maintaining self-renewal and immune evasion of cancer stem cells. FTO is overexpressed in leukemia and FTO inhibition renders leukemia cells susceptible to T-cell cytotoxicity and thus overcome immune escape (100), indicating that FTO is a prospective therapeutic target.

There has been a constant rise in both the incidence and mortality of EC. This trend is largely the result of the worldwide obesity epidemic. Obesity is more strongly associated with the progression of EC than any other group of female cancers (13). Despite the fact that the connection between obesity and EC has been confirmed by numerous studies, the molecular mechanisms underlying this association have not been fully elucidated.

FTO is overexpressed in EC and serves as an indicator of poor prognosis (101). Recently, it was reported that FTO removes m6A modification from HOXB13 mRNA, prevents YTHDF2-mediated HOXB13 from being degraded, enhances its expression, and accelerates the metastasis and invasion of EC (102), which are significant biological processes that contribute to poor prognosis (103). Mechanistically, HOXB13 is a homeobox transcription factor whose expression is increased in EC, leading to an increase in invasive capacity. It is possible that HOXB13 contributes to the promotion of tumor metastasis during the course of tumor development. FTO may catalyze the demethylation of the HOXB13 mRNA 3' UTR region, which inhibits the recognition of m6A modifications by YTHDF2, preventing the degradation of HOXB13 mRNA, increasing its expression and thereby activating the WNT signaling pathway, and thus promoting EC invasion and metastasis.

In addition, growing evidence suggests a connection between long-term estrogen exposure and the development of type I EC. Estrogen is still regarded as a significant factor in abnormal hyperplasia and tumorigenesis, as in the absence of progesterone antagonism, constant estrogen stimulation results in abnormal hyperplasia of endometrial epithelial cells (104).

Zhang et al (101) discovered that estradiol may induce FTO expression and upregulate MMP-2, MMP-9 and cyclin D1 expression by binding to estrogen receptors (ER) and activating the PI3K/AKT and MAPK signaling pathways, promoting the proliferation and invasion of EC cells.

Zhu et al (105) further determined that estrogen may promote FTO protein nuclear localization and promote proliferation through the mTOR signaling pathway in EC cells. The possible mechanism is presented in Fig. 3.


ALKBH5, another RNA demethylase, is involved in the pathological processes of several types of cancer. In glioblastoma stem-like cells (GSCs), ALKBH5 expression is upregulated, which in turn increases FOXM1 expression, maintaining the tumorigenicity of GSCs and being indicative of poor prognosis (106). Similarly, under intermittent hypoxia, ALKBH5 downregulated m6A modification, increased FOXM1 expression and promoted the proliferation and invasion of lung adenocarcinoma cells (107). ALKBH5 promotes tumorigenesis and self-renewal of tumor stem cells in acute myeloid leukemia (AML) and its increased expression is also associated with poor prognostic outcomes in AML (108). In addition, ALKBH5 has been reported as a target of HIF-1α (109). Hypoxia induces ALKBH5 expression in breast cancer cells. HIF-dependent ALKBH5 stabilizes NANOG mRNA by removing m6A methylation and induces a breast cancer stem cell phenotype (110). By contrast, ALKBH5 levels were low in most pancreatic cancer (PC) samples. Deletion of ALKBH5 is a feature of the occurrence and adverse clinicopathological findings of patients with PC. ALKBH5 activates PER1 through m6A demethylation in a YTHDF2-dependent manner, thereby inhibiting tumor proliferation and invasion and preventing PC progression (111). In conclusion, ALKBH5 exerts differential effects in different tumor types through complex mechanisms. ALKBH5 is significantly upregulated in EC. Pu et al (112) found that downregulation ALKBH5 inhibited the growth and invasive ability of EC cells and IGF1R expression regulation is a crucial intermediate mechanism of these ALKBH5-mediated alterations in endometrial cell invasion. Mechanistically, ALKBH5 primarily regulates the demethylation of IGF1R, thereby stabilizing IGF1R mRNA and promoting its translation, and activating the IGF1R signaling pathway, which in turn stimulated the production of COL1A1 and MMP9 and promoted the proliferation and invasion of EC, indicating that it is a potential target for the treatment of EC.

Furthermore, alterations to IGF1 expression and signaling are crucial for regulating normal uterine physiology (112). Elevated levels of IGF1 and hyperinsulinemia are involved in the pathogenesis of EC. Endometrial hyperplasia is associated with increased insulin and IGF1 receptor expression, which increases the susceptibility of these cells to insulin and IGF1 and promotes the hyperactivity of MAPK and PI3K/AKT/mTOR signaling frequently observed in EC (13).

Chen et al (113) indicated that ALKBH5 promoted SOX2 transcription through HIF-dependent m6A demethylation, maintaining the EC stem cell (ECSC) status and tumor characteristics. ECSCs are stem cell-like cells with the ability to differentiate and self-renew, which are essential for the progression of EC. Under hypoxic conditions, the levels of ALKBH5 are significantly increased in ECSCs, which decreases m6A levels and promotes SOX2 expression. SOX2 is a core stem cell transcription factor and mediates the early steps of tumorigenesis. In summary, these studies suggest that the HIF-ALKBH5-SOX2 axis mediated by m6A methylation has a crucial function in the process of ECSC expansion under hypoxic conditions. ALKBH5, as a promising therapeutic target, highlights novel avenues for the clinical treatment of malignant tumors.


YTHDF2 is an m6A reader protein that accelerates the degradation of m6A-modified transcripts (50). Several tumors have been indicated to abnormally express YTHDF2, including ovarian cancer (114,115), cervical cancer (116), gastric carcinoma (117) and hepatocellular carcinoma (118).

YTHDF2 was significantly upregulated in EC. According to Hong et al (119), YTHDF2 knockdown markedly accelerated endometrial cell proliferation, migration and invasion. Conversely, overexpression of YTHDF2 exerted a significant inhibitory role, indicating that YTHDF2 may inhibit the activity of EC cells. Furthermore, they confirmed that knockdown of YTHDF2 increased MMP9 expression. In subsequent studies, based on m6A-seq data, it was indicated that insulin receptor substrate 1 (IRS1) had m6A methylation modifications in EC. By immunoprecipitation, the presence of m6A sites on the IRS1 transcript was confirmed and it was indicated that YTHDF2 inhibited the activity of EC cells likely through inhibition of MMP9 expression in an IRS1-dependent manner.

IRSs, including IRS1 and IRS2, have a central role in the insulin signaling cascade by linking insulin and IGF1R to PI3K/AKT activation (120). According to reports, IRS1 is critical for cancer cell hyperplasia and mediates drug resistance, while IRS2 primarily affects the motility and metastasis of cancer cells (121). IRS1 and IRS2 phosphorylation attracts downstream factors to activate the MAPK and PI3K cascades (122).

Mechanistically, YTHDF2 promotes the degradation of IRS1 mRNA, thereby inhibiting its expression, leading to the inhibition of the AKT/MMP9 signaling pathway, ultimately inhibiting the activity of EC cells (119). When YTHDF2 was knocked down, IRS1 expression was increased and the AKT signaling pathway was activated. These results indicate that YTHDF2 may be a tumor suppressor.

Conversely, Shen et al (123) found that the degradation of long ncRNA (lncRNA) FENDRR mediated by YTHDF2 stimulated cell proliferation in EC. NcRNAs are associated with m6A modification, thereby affecting gene expression and the development of cancer (124). LncRNA FENDRR is a well-known tumor suppressor gene in several malignancies, including breast cancer (125), colon cancer (126) and prostate cancer (127). Dysregulation of lncRNA FENDDR is closely associated with the development of several types of cancer, including EC. Recently, lncRNA FENDRR was identified as an aberrantly expressed molecule in ERα-related EC (68), although the mechanisms of action remain elusive.

According to Shen et al (123), EC tissues had higher levels of m6A methylation of the lncRNA FENDRR, whilst exhibiting lower levels of lncRNA FENDRR expression. In vitro and in vivo experiments indicated that YTHDF2 recognized the m6A-modified lncRNA FENDRR and promoted its degradation. Overexpression of lncRNA FENDRR inhibited the proliferation and promoted the apoptosis of the EC cells by decreasing SOX4 protein levels.

In conclusion, the higher levels of m6A modification of lncRNA FENDRR in EC tissues promote the degradation of lncRNA FENDRR, reducing its expression by recruiting YTHDF2. Subsequently, SOX4 protein accumulates, which promotes the proliferation of EC cells. These findings suggest that YTHDF2 may be an oncogene.

In addition, atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (EAH/EIN) has a higher risk of developing into endometrioid adenocarcinoma (EMAC) than endometrial hyperplasia without atypia (EHWA) and is considered a precancerous lesion of EMAC.

According to Bian et al (128), YTHDF2 was weakly expressed in the normal endometrium and EHWA, whilst being upregulated in EAH/EIN and EMAC, indicating that YTHDF2 may be a valuable marker for differentiating between EAH/EIN and EHWA, which makes earlier clinical detection and intervention of these precancerous lesions possible.


IGF2BPs, including IGF2BP1/2/3, are a distinct group of m6A readers that are able to identify m6A modifications (64). IGF2BPs influence gene regulation and cancer biology by enhancing the stability and storage of their target mRNAs. IGF2BP1 is a conserved oncogenic driver with significantly upregulated expression in various types of cancer (129,130).

It was discovered that IGF2BP1 has a critical part in the regulation of EC through the recognition of m6A-modified PEG10 mRNA. IGF2BP1 mRNA expression was significantly higher in EC tissues than in normal tissues and it was associated with unfavorable prognosis, tumor grade and stage (131). IGF2BP1 regulates the tumor cell cycle and tumor growth and is able to stimulate or inhibit cell proliferation when it is upregulated or knocked down, respectively.

Zhang et al (132) indicated that IGF2BP1 is able to recognize and interact with PEG10 mRNA and promote PEG10 mRNA stability and expression. The stability of PEG10 mRNA and protein expression were both markedly decreased when IGF2BP1 was silenced. They further indicated that PABPC1 functions in this mechanism in a synergistic manner. PABPC1 is a typical poly-A binding protein that is able to bind to and stabilize mRNA, preventing the mRNA tail from being cut off by nucleases (133). PEG10 is suspected to be an oncogene that has a role in tumor cell proliferation, apoptosis and metastasis (134). Previous research suggested that PEG10 is overexpressed in several diseases, including liver cancer, pancreatic cancer and bladder cancer (135-137).

According to research by Zhang et al (132), PEG10 was upregulated in EC and was directly associated with the survival rate. Mechanistically, IGF2BP1 recognizes the m6A modification of the 3'UTR of PEG10 mRNA and recruits PABPC1 to synergistically stabilize PEG10 mRNA to promote its protein expression and proliferation of EC cells. Furthermore, a significant portion of the PEG10 protein binds to the p16 and p18 promoter regions, limiting RNA and protein expression and increasing cell cycle progression.

According to Xue et al (67), MEK1 citrullination caused by PADI2 activates ERK1/2 and helps IGF2BP1 to stabilize SOX2 mRNA in EC. In fact, several different malignancies have been reported to exhibit upregulation of PADIs compared with the respective healthy tissues (138). PADI2 converts arginine to citrulline; its expression is positively associated with the development of EC and it is required for proliferation, migration and invasion.

Mechanistically, PADI2 interacts with and catalyzes MEK1 citrullination, which activates ERK1/2, thereby increasing the expression of IGF2BP1. IGF2BP1 enhances the stability of SOX2 mRNA. There is an enrichment of three nonredundant m6A sites (GGACH) around the 3'UTR of the SOX2 gene and m6A modification on these three sites stabilizes SOX2 mRNA and increases its protein expression. IGF2BP1 binds to these three m6A sites to maintain the stability of the transcripts and prevent SOX2 mRNA degradation. Aberrant expression of IGF2BP1 mediated by PADI2/MEK1/ERK signaling leads to the accumulation of SOX2, supporting the malignant state of EC. Thus, patients with EC may benefit from a therapeutic strategy that targets the PADI2/MEK1/ERK/IGF2BP1 axis (67).

Other m6A regulators in EC

The prognosis of EC is tightly associated with changes in the m6A regulator, whose alterations may serve as a valid and trustworthy marker for EC prognosis (139,140). According to research by Ma et al (131), the expression of ZC3H13, YTHDC1 and METTL14 in EC tissues was significantly decreased, which were thus considered potential diagnostic and prognostic biomarkers for EC. The expression of ZC3H13, YTHDC1 and METTL14 in EC tissues is positively correlated with PD-L1 expression; PD-L1 interacts with PD-1 to suppress anti-tumor immunity, while blocking PD-L1/PD-1 interaction significantly enhances the anti-tumor immune response (141), indicating that blocking these proteins may enhance the effects of immunotherapy.

According to Zhai et al (142), RBM15/15B, YTHDF1 and IGF2BP1/2 are upregulated in endometrial adenocarcinoma. By contrast, FTO, KIAA1429, METTL14, ZC3H13 and YTHDC1 expression was downregulated. In their study, decreased FTO expression in tumors conflicted with previous findings; they speculated that this discrepancy may be related to the pathological type of EC used in their study. RBM15, FTO and YTHDF1 were identified as prognostic biomarkers in EC that may be involved in cell cycle regulation, affect RNA processing and translation, and contribute to tumor-associated processes and prognosis of endometrial adenocarcinoma. However, the exact mechanisms of these regulators have remained to be fully elucidated and further study is required.

5. Conclusions and future perspectives

At present, the primary treatment of EC comprises surgery, radiation and chemotherapy. These conventional treatment methods may result in trauma for patients and the adverse reactions of radiotherapy and chemotherapy are well documented, which seriously affect the quality of a patient's life.

As a hot topic in epigenetics, m6A modifications have attracted considerable attention, providing us with novel ideas and methods for the treatment of EC. A total of three types of regulators carry out the dynamic reversible m6A modification process: Methyltransferases (referred to as writers), demethylases (referred to as erasers) and m6A binding proteins (referred to as readers). Through these regulators, splicing, translation, stability and the decay of mRNAs are regulated. Oncogenes and tumor suppressor genes are regulated by m6A modifications, which have an impact on the occurrence and development of malignancies. At the same time, m6A modification may affect its role in cancer by regulating the levels of m6A modifications and the expression of regulators. Therefore, m6A regulators are anticipated to become potential targets for cancer therapy. Recent research has indicated that the expression of multiple m6A regulators is either up- or downregulated in EC, and m6A methylation, as well as related regulators, are critical in the development and progression of EC.

Despite the fact that m6A modifications were initially identified in the 1970s (143), its function was not investigated in detail until ~2012. The development of high-throughput sequencing technologies has made it easier than ever to study RNA modifications (144) and has provided a necessary basis for elucidating the unique molecular characteristics of transcriptomes on m6A (145). Future studies using m6A-seq and MeRIP will help to deeper analyze m6A regulators in EC. By determining the genetic risk prognosis model to forecast the rate of survival of patients with EC, certain m6A regulatory factors may be employed as promising markers to predict clinical outcomes of cancer patients and offer a theoretical foundation or target for the treatment of EC.

The present review summarized the primary functions of the significant m6A regulators in EC, with the aim of providing novel methods and approaches for the diagnosis or prognosis of EC. To date, certain small chemical molecule inhibitors that target m6A regulators have demonstrated considerable promise for preventing the growth of cancer (7). For instance, R-2-hydroxyglutarate (R-2HG) reduces FTO activity and raises m6A levels in R-2HG-sensitive leukemia cells, further reducing the stability of MYC/CEBPA transcripts and finally inhibiting the activity of leukemia cells, promoting cell cycle arrest and apoptosis, and exerting anti-leukemic effects (146). Carbonic anhydrase IV interacts with WTAP and promotes WTAP protein degradation, facilitates the transcriptional activity of WT1, an inhibitor of the WNT pathway, and inhibits the occurrence and development of colon cancer (147). In general, m6A regulator-specific inhibitors offer a potentially valuable alternative approach for cancer treatment.

The research on m6A in EC is still in its early stages and there are numerous up- and downstream m6A regulators whose precise mechanisms remain elusive and require to be investigated. In addition, the changes in the levels of certain m6A regulators were demonstrated to be closely related to the prognosis of EC and different types of EC with different molecular characteristics also have different prognoses. We speculate whether there are any differences in m6A RNA methylation levels, the expression of regulatory factors, and related mechanisms in different molecular types of EC. At present, the research on RNA m6A methylation in different molecular types of EC is still insufficient. It is hypothesized that m6A regulators will serve as valuable targets for cancer therapy and offer novel approaches for treating malignancies. However, the clinical application of m6A-based cancer treatment requires a considerable amount of research before these treatments may be used in the clinic.

Availability of data and materials

Not applicable.

Authors' contributions

JT and JG designed the study. SS selected/searched the literature and drafted the manuscript. NL and QC revised the manuscript. All authors have read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.


Not applicable.


This work was supported by a special research fund for gynecological oncology 'Le Foundation' (grant no. KH-2021-LZJJ-001).



Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI


Crosbie EJ, Kitson SJ, McAlpine JN, Mukhopadhyay A, Powell ME and Singh N: Endometrial cancer. Lancet. 399:1412–1428. 2022. View Article : Google Scholar : PubMed/NCBI


MacKay HJ, Freixinos VR and Fleming GF: Therapeutic targets and opportunities in endometrial cancer: Update on endocrine therapy and nonimmunotherapy targeted options. Am Soc Clin Oncol Educ Book. 40:1–11. 2020.PubMed/NCBI


Yang J, Chen J, Fei X, Wang X and Wang K: N6-methyladenine RNA modification and cancer. Oncol Lett. 20:1504–1512. 2020. View Article : Google Scholar : PubMed/NCBI


Zhou Z, Lv J, Yu H, Han J, Yang X, Feng D, Wu Q, Yuan B, Lu Q and Yang H: Mechanism of RNA modification N6-methyladenosine in human cancer. Mol Cancer. 19:1042020. View Article : Google Scholar : PubMed/NCBI


Yang G, Sun Z and Zhang N: Reshaping the role of m6A modification in cancer transcriptome: A review. Cancer Cell Int. 20:3532020. View Article : Google Scholar : PubMed/NCBI


Han X, Wang M, Zhao YL, Yang Y and Yang YG: RNA methylations in human cancers. Semin Cancer Biol. 75:97–115. 2021. View Article : Google Scholar


Shen S, Zhang R, Jiang Y, Li Y, Lin L, Liu Z, Zhao Y, Shen H, Hu Z, Wei Y and Chen F: Comprehensive analyses of m6A regulators and interactive coding and non-coding RNAs across 32 cancer types. Mol Cancer. 20:672021. View Article : Google Scholar : PubMed/NCBI


Yu AM, Jian C, Yu AH and Tu MJ: RNA therapy: Are we using the right molecules? Pharmacol Ther. 196:91–104. 2019. View Article : Google Scholar :


Arend RC, Jones BA, Martinez A and Goodfellow P: Endometrial cancer: Molecular markers and management of advanced stage disease. Gynecol Oncol. 150:569–580. 2018. View Article : Google Scholar : PubMed/NCBI


Gu B, Shang X, Yan M, Li X, Wang W, Wang Q and Zhang C: Variations in incidence and mortality rates of endometrial cancer at the global, regional, and national levels, 1990-2019. Gynecol Oncol. 161:573–580. 2021. View Article : Google Scholar : PubMed/NCBI


Ryan NAJ, Glaire MA, Blake D, Cabrera-Dandy M, Evans DG and Crosbie EJ: The proportion of endometrial cancers associated with Lynch syndrome: A systematic review of the literature and meta-analysis. Genet Med. 21:2167–2180. 2019. View Article : Google Scholar : PubMed/NCBI


Onstad MA, Schmandt RE and Lu KH: Addressing the role of obesity in endometrial cancer risk, prevention, and treatment. J Clin Oncol. 34:4225–4230. 2016. View Article : Google Scholar : PubMed/NCBI


Hecht JL and Mutter GL: Molecular and pathologic aspects of endometrial carcinogenesis. J Clin Oncol. 24:4783–4791. 2006. View Article : Google Scholar : PubMed/NCBI


Bansal N, Yendluri V and Wenham RM: The molecular biology of endometrial cancers and the implications for pathogenesis, classification, and targeted therapies. Cancer Control. 16:8–13. 2009. View Article : Google Scholar


Brooks RA, Fleming GF, Lastra RR, Lee NK, Moroney JW, Son CH, Tatebe K and Veneris JL: Current recommendations and recent progress in endometrial cancer. CA Cancer J Clin. 69:258–279. 2019.PubMed/NCBI


León-Castillo A, Gilvazquez E, Nout R, Smit VT, McAlpine JN, McConechy M, Kommoss S, Brucker SY, Carlson JW, Epstein E, et al: Clinicopathological and molecular characterisation of 'multiple-classifier' endometrial carcinomas. J Pathol. 250:312–322. 2020. View Article : Google Scholar


Bell DW and Ellenson LH: Molecular genetics of endometrial carcinoma. Annu Rev Pathol. 14:339–367. 2019. View Article : Google Scholar


Wang M and Hui P: A timely update of immunohistochemistry and molecular classification in the diagnosis and risk assessment of endometrial carcinomas. Arch Pathol Lab Med. 145:1367–1378. 2021. View Article : Google Scholar : PubMed/NCBI


Cancer Genome Atlas Research Network; Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, et al: Integrated genomic characterization of endometrial carcinoma. Nature. 497:67–73. 2013. View Article : Google Scholar : PubMed/NCBI


Murali R, Soslow RA and Weigelt B: Classification of endometrial carcinoma: more than two types. Lancet Oncol. 15:e268–e278. 2014. View Article : Google Scholar : PubMed/NCBI


Winterhoff B, Thomaier L, Mullany S and Powell MA: Molecular characterization of endometrial cancer and therapeutic implications. Curr Opin Obstet Gynecol. 32:76–83. 2020. View Article : Google Scholar


Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bettio M, Gavin A, Visser O and Bray F: Cancer incidence and mortality patterns in Europe Estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer. 103:356–387. 2018. View Article : Google Scholar : PubMed/NCBI


McAlpine JN, Temkin SM and Mackay HJ: Endometrial cancer: Not your grandmother's cancer. Cancer. 122:2787–2798. 2016. View Article : Google Scholar : PubMed/NCBI


Hazelwood E, Sanderson E, Tan VY, Ruth KS, Frayling TM, Dimou N, Gunter MJ, Dossus L, Newton C, Ryan N, et al: Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: A mendelian randomization analysis. BMC Med. 20:1252022. View Article : Google Scholar : PubMed/NCBI


Merritt MA, Strickler HD, Hutson AD, Einstein MH, Rohan TE, Xue X, Sherma ME, Brinton LA, Yu H, Miller DS, et al: Sex hormones, insulin, and insulin-like growth factors in recurrence of high-stage endometrial cancer. Cancer Epidemiol Biomarkers Prev. 30:719–726. 2021. View Article : Google Scholar : PubMed/NCBI


Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE and Jaffrey SR: Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons. Cell. 149:1635–1646. 2012. View Article : Google Scholar : PubMed/NCBI


Huang H, Weng H and Chen J: m6A modification in coding and non-coding RNAs: Roles and therapeutic implications in cancer. Cancer Cell. 37:270–288. 2020. View Article : Google Scholar : PubMed/NCBI


Huang H, Weng H and Chen J: The biogenesis and precise control of RNA m6A methylation. Trends Genet. 36:44–52. 2020. View Article : Google Scholar


Wang T, Kong S, Tao M and Ju S: The potential role of RNA N6-methyladenosine in cancer progression. Mol Cancer. 19:882020. View Article : Google Scholar : PubMed/NCBI


He L, Li H, Wu A, Peng Y, Shu G and Yin G: Functions of N6-methyladenosine and its role in cancer. Mol Cancer. 18:1762019. View Article : Google Scholar : PubMed/NCBI


Hu Y, Wang S, Liu J, Huang Y, Gong C, Liu J, Xiao Y and Yang S: New sights in cancer: Component and function of N6-methyladenosine modification. Biomed Pharmacother. 122:1096942020. View Article : Google Scholar : PubMed/NCBI


He PC and He C: m6 A RNA methylation: From mechanisms to therapeutic potential. EMBO J. 40:e1059772021. View Article : Google Scholar


Lin S, Choe J, Du P, Triboulet R and Gregory RI: The m(6)A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell. 62:335–345. 2016. View Article : Google Scholar : PubMed/NCBI


Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, et al: A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 10:93–95. 2014. View Article : Google Scholar :


Huang J, Dong X, Gong Z, Qin LY, Yang S, Zhu YL, Wang X, Zhang D, Zou T, Yin P and Tang C: Solution structure of the RNA recognition domain of METTL3-METTL14 N6-methyladenosine methyltransferase. Protein Cell. 10:272–284. 2019. View Article : Google Scholar


Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, et al: Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 24:177–189. 2014. View Article : Google Scholar : PubMed/NCBI


Yue Y, Liu J, Cui X, Cao J, Luo G, Zhang Z, Cheng T, Gao M, Shu X, Ma H, et al: VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell Discov. 4:102018. View Article : Google Scholar


Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M and Jaffrey SR: m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 537:369–373. 2016. View Article : Google Scholar : PubMed/NCBI


Zhu D, Zhou J, Zhao J, Jiang G, Zhang X, Zhang Y and Dong M: ZC3H13 suppresses colorectal cancer proliferation and invasion via inactivating Ras-ERK signaling. J Cell Physiol. 234:8899–8907. 2019. View Article : Google Scholar


Wen J, Lv R, Ma H, Shen H, He C, Wang J, Jiao F, Liu H, Yang P, Tan L, et al: Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell self-renewal. Mol Cell. 69:1028–1038.e6. 2018. View Article : Google Scholar


Shen D, Wang B, Gao Y, Zhao L, Bi Y, Zhang J, Wang N, Kang H, Pang J, Liu Y, et al: Detailed resume of RNA m6A demethylases. Acta Pharm Sin B. 12:2193–2205. 2022. View Article : Google Scholar : PubMed/NCBI


Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG and He C: N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 7:885–887. 2011. View Article : Google Scholar : PubMed/NCBI


Wei J, Liu F, Lu Z, Fei Q, Ai Y, He PC, Shi H, Cui X, Su R, Klungland A, et al: Differential m6A, m6Am m, and m1A demethylation mediated by FTO in the cell nucleus and cytoplasm. Mol Cell. 71:973–985.e5. 2018. View Article : Google Scholar


Bartosovic M, Molares HC, Gregorova P, Hrossova D, Kudla G and Vanacova S: N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3'-end processing. Nucleic Acids Res. 45:11356–11370. 2017. View Article : Google Scholar : PubMed/NCBI


Gao S, Li X, Zhang M, Zhang N, Wang R and Chang J: Structural characteristics of small-molecule inhibitors targeting FTO demethylase. Future Med Chem. 13:1475–1489. 2021. View Article : Google Scholar : PubMed/NCBI


Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vågbø CB, Shi Y, Wang WL, Song SH, et al: ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 49:18–29. 2013. View Article : Google Scholar :


Qu J, Yan H, Hou Y, Cao W, Liu Y, Zhang E, He J and Cai Z: RNA demethylase ALKBH5 in cancer: From mechanisms to therapeutic potential. J Hematol Oncol. 15:82022. View Article : Google Scholar : PubMed/NCBI


Zhao Y, Shi Y, Shen H and Xie W: m6A-binding proteins: The emerging crucial performers in epigenetics. J Hematol Oncol. 13:352020. View Article : Google Scholar


Du H, Zhao Y, He J, Zhang Y, Xi H, Liu M, Ma J and Wu L: YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat Commun. 7:126262016. View Article : Google Scholar : PubMed/NCBI


Liu J, Gao M, Xu S, Chen Y, Wu K, Liu H, Wang J, Yang X, Wang J, Liu W, et al: YTHDF2/3 are required for somatic reprogramming through different RNA deadenylation pathways. Cell Rep. 32:1081202020. View Article : Google Scholar : PubMed/NCBI


Zhou J, Wan J, Gao X, Zhang X, Jaffrey SR and Qian SB: Dynamic m(6)A mRNA methylation directs translational control of heat shock response. Nature. 526:591–594. 2015. View Article : Google Scholar : PubMed/NCBI


Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K, Shi H and He C: N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 161:1388–1399. 2015. View Article : Google Scholar : PubMed/NCBI


Chen Z, Zhong X, Xia M and Zhong J: The roles and mechanisms of the m6A reader protein YTHDF1 in tumor biology and human diseases. Mol Ther Nucleic Acids. 26:1270–1279. 2021. View Article : Google Scholar : PubMed/NCBI


Shi H, Wang X, Lu Z, Zhao BS, Ma H, Hsu PJ, Liu C and He C: YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell Res. 27:315–328. 2017. View Article : Google Scholar : PubMed/NCBI


Li A, Chen YS, Ping XL, Yang X, Xiao W, Yang Y, Sun HY, Zhu Q, Baidya P, Wang X, et al: Cytoplasmic m6A reader YTHDF3 promotes mRNA translation. Cell Res. 27:444–447. 2017. View Article : Google Scholar : PubMed/NCBI


Li S, Qi Y, Yu J, Hao Y, He B, Zhang M, Dai Z, Jiang T, Li S, Huang F, et al: Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4. Signal Transduct Target Ther. 7:972022. View Article : Google Scholar


Kim GW, Imam H and Siddiqui A: The RNA binding proteins YTHDC1 and FMRP regulate the nuclear export of N6-methyladenosine-modified hepatitis B virus transcripts and affect the viral life cycle. J Virol. 95:e00097212021. View Article : Google Scholar


Shima H, Matsumoto M, Ishigami Y, Ebina M, Muto A, Sato Y, Kumagai S, Ochiai K, Suzuki T and Igarashi K: S-adenosylmethionine synthesis is regulated by selective N6-adenosine methylation and mRNA degradation involving METTL16 and YTHDC1. Cell Rep. 21:3354–3363. 2017. View Article : Google Scholar : PubMed/NCBI


Hsu PJ, Zhu Y, Ma H, Guo Y, Shi X, Liu Y, Qi M, Lu Z, Shi H, Wang J, et al: Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 27:1115–1127. 2017. View Article : Google Scholar : PubMed/NCBI


Alarcón CR, Goodarzi H, Lee H, Liu X, Tavazoie S and Tavazoie SF: HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell. 162:1299–1308. 2015. View Article : Google Scholar : PubMed/NCBI


Liu N, Dai Q, Zheng G, He C, Parisien M and Pan T: N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 518:560–564. 2015. View Article : Google Scholar : PubMed/NCBI


Liu N, Zhou KI, Parisien M, Dai Q, Diatchenko L and Pan T: N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein. Nucleic Acids Res. 45:6051–6063. 2017. View Article : Google Scholar : PubMed/NCBI


Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, Zhao BS, Mesquita A, Liu C, Yuan CL, et al: Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 20:285–295. 2018. View Article : Google Scholar : PubMed/NCBI


Song K, Xu H and Wang C: The role of N6-methyladenosine methylation in the progression of endometrial cancer. Cancer Biother Radiopharm. Oct 14–2020.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI


Lan Q, Liu PY, Haase J, Bell JL, Hüttelmaier S and Liu T: The critical role of RNA m6A methylation in cancer. Cancer Res. 79:1285–1292. 2019. View Article : Google Scholar : PubMed/NCBI


Xue T, Liu X, Zhang M, E Q, Liu S, Zou M, Li Y, Ma Z, Han Y, Thompson P and Zhang X: PADI2-catalyzed MEK1 citrullination activates ERK1/2 and promotes IGF2BP1-mediated SOX2 mRNA stability in endometrial cancer. Adv Sci (Weinh). 8:20028312021. View Article : Google Scholar


Liu A, Zhang D, Yang X and Song Y: Estrogen receptor alpha activates MAPK signaling pathway to promote the development of endometrial cancer. J Cell Biochem. 120:17593–17601. 2019. View Article : Google Scholar : PubMed/NCBI


Barra F, Evangelisti G, Ferro Desideri L, Di Domenico S, Ferraioli D, Vellone VG, De Cian F and Ferrero S: Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer. Expert Opin Investig Drugs. 28:131–142. 2019. View Article : Google Scholar


Wang Y, Yin L and Sun X: CircRNA hsa_circ_0002577 accelerates endometrial cancer progression through activating IGF1R/PI3K/Akt pathway. J Exp Clin Cancer Res. 39:1692020. View Article : Google Scholar : PubMed/NCBI


Zhao BS, Roundtree IA and He C: Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 18:31–42. 2017. View Article : Google Scholar


Hu C, Liu J, Li Y, Jiang W, Ji D, Liu W and Ma T: Multifaceted roles of the N6-methyladenosine RNA methyltransferase METTL3 in cancer and immune microenvironment. Biomolecules. 12:10422022. View Article : Google Scholar


Zheng W, Dong X, Zhao Y, Wang S, Jiang H, Zhang M, Zheng X and Gu M: Multiple functions and mechanisms underlying the role of METTL3 in human cancers. Front Oncol. 9:14032019. View Article : Google Scholar


Wei W, Huo B and Shi X: miR-600 inhibits lung cancer via downregulating the expression of METTL3. Cancer Manag Res. 11:1177–1187. 2019. View Article : Google Scholar : PubMed/NCBI


Vu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, Chou T, Chow A, Saletore Y, MacKay M, et al: The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 23:1369–1376. 2017. View Article : Google Scholar : PubMed/NCBI


Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millán-Zambrano G, Robson SC, Aspris D, Migliori V, Bannister AJ, Han N, et al: Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature. 552:126–131. 2017. View Article : Google Scholar : PubMed/NCBI


Liu T, Yang S, Sui J, Xu SY, Cheng YP, Shen B, Zhang Y, Zhang XM, Yin LH, Pu YP and Liang GY: Dysregulated N6-methyladenosine methylation writer METTL3 contributes to the proliferation and migration of gastric cancer. J Cell Physiol. 235:548–562. 2020. View Article : Google Scholar


Yue B, Song C, Yang L, Cui R, Cheng X, Zhang Z and Zhao G: METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Mol Cancer. 18:1422019. View Article : Google Scholar : PubMed/NCBI


Hua W, Zhao Y, Jin X, Yu D, He J, Xie D and Duan P: METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition. Gynecol Oncol. 151:356–365. 2018. View Article : Google Scholar : PubMed/NCBI


Li X, Tang J, Huang W, Wang F, Li P, Qin C, Qin Z, Zou Q, Wei J, Hua L, et al: The M6A methyltransferase METTL3: Acting as a tumor suppressor in renal cell carcinoma. Oncotarget. 8:96103–96116. 2017. View Article : Google Scholar : PubMed/NCBI


Cheng M, Sheng L, Gao Q, Xiong Q, Zhang H, Wu M, Liang Y, Zhu F, Zhang Y, Zhang X, et al: The m6A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network. Oncogene. 38:3667–3680. 2019. View Article : Google Scholar : PubMed/NCBI


Han J, Wang JZ, Yang X, Yu H, Zhou R, Lu HC, Yuan WB, Lu JC, Zhou ZJ, Lu Q, et al: METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner. Mol Cancer. 18:1102019. View Article : Google Scholar : PubMed/NCBI


Zhao S, Liu J, Nanga P, Liu Y, Cicek AE, Knoblauch N, He C, Stephens M and He X: Detailed modeling of positive selection improves detection of cancer driver genes. Nat Commun. 10:33992019. View Article : Google Scholar : PubMed/NCBI


Cai X, Wang X, Cao C, Gao Y, Zhang S, Yang Z, Liu Y, Zhang X, Zhang W and Ye L: HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g. Cancer Lett. 415:–19. 2018. View Article : Google Scholar


Wu L, Wu D, Ning J, Liu W and Zhang D: Changes of N6-methyladenosine modulators promote breast cancer progression. BMC Cancer. 19:3262019. View Article : Google Scholar : PubMed/NCBI


Liu J, Eckert MA, Harada BT, Liu SM, Lu Z, Yu K, Tienda SM, Chryplewicz A, Zhu AC, Yang Y, et al: m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat Cell Biol. 20:1074–1083. 2018. View Article : Google Scholar : PubMed/NCBI


Manning BD and Toker A: AKT/PKB signaling: Navigating the network. Cell. 169:381–405. 2017. View Article : Google Scholar : PubMed/NCBI


Xue C, Li G, Lu J and Li L: Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression. Signal Transduct Target Ther. 6:4002021. View Article : Google Scholar : PubMed/NCBI


Engelman JA, Luo J and Cantley LC: The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 7:606–619. 2006. View Article : Google Scholar : PubMed/NCBI


Ralser DJ, Condic M, Klümper N, Ellinger J, Staerk C, Egger EK, Kristiansen G, Mustea A and Thiesler T: Comprehensive immunohistochemical analysis of N6-methyladenosine (m6A) writers, erasers, and readers in endometrial cancer. J Cancer Res Clin Oncol. Jun 22–2022.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI


Yu HL, Ma XD, Tong JF, Li JQ, Guan XJ and Yang JH: WTAP is a prognostic marker of high-grade serous ovarian cancer and regulates the progression of ovarian cancer cells. Onco Targets Ther. 12:6191–6201. 2019. View Article : Google Scholar : PubMed/NCBI


Kuai Y, Gong X, Ding L, Li F, Lei L, Gong Y, Liu Q, Tan H, Zhang X, Liu D, et al: Wilms' tumor 1-associating protein plays an aggressive role in diffuse large B-cell lymphoma and forms a complex with BCL6 via Hsp90. Cell Commun Signal. 16:502018. View Article : Google Scholar : PubMed/NCBI


Tang J, Wang F, Cheng G, Si S, Sun X, Han J, Yu H, Zhang W, Lv Q, Wei JF and Yang H: Wilms' tumor 1-associating protein promotes renal cell carcinoma proliferation by regulating CDK2 mRNA stability. J Exp Clin Cancer Res. 37:402018. View Article : Google Scholar : PubMed/NCBI


Chen Y, Peng C, Chen J, Chen D, Yang B, He B, Hu W, Zhang Y, Liu H, Dai L, et al: WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1. Mol Cancer. 18:1272019. View Article : Google Scholar : PubMed/NCBI


Yu H, Zhao K, Zeng H, Li Z, Chen K, Zhang Z, Li E and Wu Z: N6-methyladenosine (m6A) methyltransferase WTAP accelerates the Warburg effect of gastric cancer through regulating HK2 stability. Biomed Pharmacother. 133:1110752021. View Article : Google Scholar


Li Q, Wang C, Dong W, Su Y and Ma Z: WTAP facilitates progression of endometrial cancer via CAV-1/NF-κB axis. Cell Biol Int. 45:1269–1277. 2021. View Article : Google Scholar : PubMed/NCBI


Azzam SK, Alsafar H and Sajini AA: FTO m6A demethylase in obesity and cancer: Implications and underlying molecular mechanisms. Int J Mol Sci. 23:38002022. View Article : Google Scholar : PubMed/NCBI


Deng X, Su R, Stanford S and Chen J: Critical enzymatic functions of FTO in obesity and cancer. Front Endocrinol (Lausanne). 9:3962018. View Article : Google Scholar


Tao L, Mu X, Chen H, Jin D, Zhang R, Zhao Y, Fan J, Cao M and Zhou Z: FTO modifies the m6A level of MALAT and promotes bladder cancer progression. Clin Transl Med. 11:e3102021. View Article : Google Scholar : PubMed/NCBI


Su R, Dong L, Li Y, Gao M, Han L, Wunderlich M, Deng X, Li H, Huang Y, Gao L, et al: Targeting FTO suppresses cancer stem cell maintenance and immune evasion. Cancer Cell. 38:79–96.e11. 2020. View Article : Google Scholar : PubMed/NCBI


Zhang Z, Zhou D, Lai Y, Liu Y, Tao X, Wang Q, Zhao G, Gu H, Liao H, Zhu Y, et al: Estrogen induces endometrial cancer cell proliferation and invasion by regulating the fat mass and obesity-associated gene via PI3K/AKT and MAPK signaling pathways. Cancer Lett. 319:89–97. 2012. View Article : Google Scholar : PubMed/NCBI


Zhang L, Wan Y, Zhang Z, Jiang Y, Lang J, Cheng W and Zhu L: FTO demethylates m6A modifications in HOXB13 mRNA and promotes endometrial cancer metastasis by activating the WNT signalling pathway. RNA Biol. 18:1265–1278. 2021. View Article : Google Scholar :


Lewczuk Ł, Pryczynicz A and Guzińska-Ustymowicz K: Cell adhesion molecules in endometrial cancer-a systematic review. Adv Med Sci. 64:423–429. 2019. View Article : Google Scholar : PubMed/NCBI


Delaunay S and Frye M: RNA modifications regulating cell fate in cancer. Nat Cell Biol. 21:552–559. 2019. View Article : Google Scholar : PubMed/NCBI


Zhu Y, Shen J, Gao L and Feng Y: Estrogen promotes fat mass and obesity-associated protein nuclear localization and enhances endometrial cancer cell proliferation via the mTOR signaling pathway. Oncol Rep. 35:2391–2397. 2016. View Article : Google Scholar : PubMed/NCBI


Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bögler O, et al: m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 31:591–606.e6. 2017. View Article : Google Scholar


Chao Y, Shang J and Ji W: ALKBH5-m6A-FOXM1 signaling axis promotes proliferation and invasion of lung adenocarcinoma cells under intermittent hypoxia. Biochem Biophys Res Commun. 521:499–506. 2020. View Article : Google Scholar


Shen C, Sheng Y, Zhu AC, Robinson S, Jiang X, Dong L, Chen H, Su R, Yin Z, Li W, et al: RNA demethylase ALKBH5 selectively promotes tumorigenesis and cancer stem cell self-renewal in acute myeloid leukemia. Cell Stem Cell. 27:64–80.e9. 2020. View Article : Google Scholar : PubMed/NCBI


Thalhammer A, Bencokova Z, Poole R, Loenarz C, Adam J, O'Flaherty L, Schödel J, Mole D, Giaslakiotis K, Schofield CJ, et al: Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor 1α (HIF-1α). PLoS One. 6:e162102011. View Article : Google Scholar


Zhang C, Samanta D, Lu H, Bullen JW, Zhang H, Chen I, He X and Semenza GL: Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. Proc Natl Acad Sci USA. 113:E2047–E2056. 2016. View Article : Google Scholar


Guo X, Li K, Jiang W, Hu Y, Xiao W, Huang Y, Feng Y, Pan Q and Wan R: RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner. Mol Cancer. 19:912020. View Article : Google Scholar : PubMed/NCBI


Pu X and Gu Z and Gu Z: ALKBH5 regulates IGF1R expression to promote the proliferation and tumorigenicity of endometrial cancer. J Cancer. 11:5612–5622. 2020. View Article : Google Scholar : PubMed/NCBI


Chen G, Liu B, Yin S, Li S, Guo Y, Wang M, Wang K and Wan X: Hypoxia induces an endometrial cancer stem-like cell phenotype via HIF-dependent demethylation of SOX2 mRNA. Oncogenesis. 9:812020. View Article : Google Scholar : PubMed/NCBI


Li J, Wu L, Pei M and Zhang Y: YTHDF2, a protein repressed by miR-145, regulates proliferation, apoptosis, and migration in ovarian cancer cells. J Ovarian Res. 13:1112020. View Article : Google Scholar : PubMed/NCBI


Xu F, Li J, Ni M, Cheng J, Zhao H, Wang S, Zhou X and Wu X: FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2. Mol Cancer. 20:452021. View Article : Google Scholar


Li Z, Luo Q, Wang H, Liu Y, Feng X, Li Z and Yi P: Knockdown of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) inhibits cell proliferation and promotes apoptosis in cervical cancer cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 36:255–263. 2020.In Chinese. PubMed/NCBI


Shen X, Zhao K, Xu L, Cheng G, Zhu J, Gan L, Wu Y and Zhuang Z: YTHDF2 inhibits gastric cancer cell growth by regulating FOXC2 signaling pathway. Front Genet. 11:5920422021. View Article : Google Scholar : PubMed/NCBI


Zhong L, Liao D, Zhang M, Zeng C, Li X, Zhang R, Ma H and Kang T: YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett. 442:252–261. 2019. View Article : Google Scholar


Hong L, Pu X, Gan H, Weng L and Zheng Q: YTHDF2 inhibit the tumorigenicity of endometrial cancer via downregulating the expression of IRS1 methylated with m6A. J Cancer. 12:3809–3818. 2021. View Article : Google Scholar :


Reuveni H, Flashner-Abramson E, Steiner L, Makedonski K, Song R, Shir A, Herlyn M, Bar-Eli M and Levitzki A: Therapeutic destruction of insulin receptor substrates for cancer treatment. Cancer Res. 73:4383–4394. 2013. View Article : Google Scholar : PubMed/NCBI


Ganeff C, Chatel G, Munaut C, Frankenne F, Foidart JM and Winkler R: The IGF system in in-vitro human decidualization. Mol Hum Reprod. 15:27–38. 2009. View Article : Google Scholar


Hopkins BD, Goncalves MD and Cantley LC: Insulin-PI3K signalling: An evolutionarily insulated metabolic driver of cancer. Nat Rev Endocrinol. 16:276–283. 2020. View Article : Google Scholar : PubMed/NCBI


Shen J, Feng XP, Hu RB, Wang H, Wang YL, Qian JH and Zhou YX: N-methyladenosine reader YTHDF2-mediated long noncoding RNA FENDRR degradation promotes cell proliferation in endometrioid endometrial carcinoma. Lab Invest. 101:775–784. 2021. View Article : Google Scholar : PubMed/NCBI


Luo L, Zhen Y, Peng D, Wei C, Zhang X, Liu X, Han L and Zhang Z: The role of N6-methyladenosine-modified non-coding RNAs in the pathological process of human cancer. Cell Death Discov. 8:3252022. View Article : Google Scholar : PubMed/NCBI


Li Y, Zhang W, Liu P, Xu Y, Tang L, Chen W and Guan X: Long non-coding RNA FENDRR inhibits cell proliferation and is associated with good prognosis in breast cancer. Onco Targets Ther. 11:1403–1412. 2018. View Article : Google Scholar : PubMed/NCBI


Liu J and Du W: LncRNA FENDRR attenuates colon cancer progression by repression of SOX4 protein. Onco Targets Ther. 12:4287–4295. 2019. View Article : Google Scholar : PubMed/NCBI


Zhang YQ, Chen X, Fu CL, Zhang W, Zhang DL, Pang C, Liu M and Wang JY: FENDRR reduces tumor invasiveness in prostate cancer PC-3 cells by targeting CSNK1E. Eur Rev Med Pharmacol Sci. 23:7327–7337. 2019.PubMed/NCBI


Bian PP, Liu SY, Luo QP and Xiong ZT: YTHDF2 is a novel diagnostic marker of endometrial adenocarcinoma and endometrial atypical hyperplasia/intraepithelial neoplasia. Pathol Res Pract. 234:1539192022. View Article : Google Scholar


Müller S, Bley N, Glaß M, Busch B, Rousseau V, Misiak D, Fuchs T, Lederer M and Hüttelmaier S: IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors. Nucleic Acids Res. 46:6285–6303. 2018. View Article : Google Scholar : PubMed/NCBI


Sun CY, Cao D, Du BB, Chen CW and Liu D: The role of Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) as m6A readers in cancer. Int J Biol Sci. 18:2744–2758. 2022. View Article : Google Scholar :


Ma J, Yang D and Ma XX: Immune infiltration-related N6-methyladenosine RNA methylation regulators influence the malignancy and prognosis of endometrial cancer. Aging (Albany NY). 13:16287–16315. 2021. View Article : Google Scholar


Zhang L, Wan Y, Zhang Z, Jiang Y, Gu Z, Ma X, Nie S, Yang J, Lang J, Cheng W and Zhu L: IGF2BP1 overexpression stabilizes PEG10 mRNA in an m6A-dependent manner and promotes endometrial cancer progression. Theranostics. 11:1100–1114. 2021. View Article : Google Scholar : PubMed/NCBI


Nicholson AL and Pasquinelli AE: Tales of detailed poly(A) tails. Trends Cell Biol. 29:191–200. 2019. View Article : Google Scholar


Xie T, Pan S, Zheng H, Luo Z, Tembo KM, Jamal M, Yu Z, Yu Y, Xia J, Yin Q, et al: PEG10 as an oncogene: Expression regulatory mechanisms and role in tumor progression. Cancer Cell Int. 18:1122018. View Article : Google Scholar : PubMed/NCBI


Peng YP, Zhu Y, Yin LD, Zhang JJ, Wei JS, Liu X, Liu XC, Gao WT, Jiang KR and Miao Y: PEG10 overexpression induced by E2F-1 promotes cell proliferation, migration, and invasion in pancreatic cancer. J Exp Clin Cancer Res. 36:302017. View Article : Google Scholar : PubMed/NCBI


Li Y, Guo D, Lu G, Mohiuddin Chowdhury ATM, Zhang D, Ren M, Chen Y, Wang R and He S: LncRNA SNAI3-AS1 promotes PEG10-mediated proliferation and metastasis via decoying of miR-27a-3p and miR-34a-5p in hepatocellular carcinoma. Cell Death Dis. 11:6852020. View Article : Google Scholar : PubMed/NCBI


Kawai Y, Imada K, Akamatsu S, Zhang F, Seiler R, Hayashi T, Leong J, Beraldi E, Saxena N, Kretschmer A, et al: Paternally expressed gene 10 (PEG10) promotes growth, invasion, and survival of bladder cancer. Mol Cancer Ther. 19:2210–2220. 2020. View Article : Google Scholar : PubMed/NCBI


Chang X, Han J, Pang L, Zhao Y, Yang Y and Shen Z: Increased PADI4 expression in blood and tissues of patients with malignant tumors. BMC Cancer. 9:402009. View Article : Google Scholar : PubMed/NCBI


Pang X, Zhang X, Huang Y and Qian S: Development and validation of m6A regulators' prognostic significance for endometrial cancer. Medicine (Baltimore). 100:e265512021. View Article : Google Scholar


Wang Y, Ren F, Song Z, Wang X and Ma X: Multiomics profile and prognostic gene signature of m6A regulators in uterine corpus endometrial carcinoma. J Cancer. 11:6390–6401. 2020. View Article : Google Scholar : PubMed/NCBI


Han Y, Liu D and Li L: PD-1/PD-L1 pathway: Current researches in cancer. Am J Cancer Res. 10:727–742. 2020.PubMed/NCBI


Zhai J, Li S, Li Y and Du Y: Data mining analysis of the prognostic impact of N6-methyladenosine regulators in patients with endometrial adenocarcinoma. J Cancer. 12:4729–4738. 2021. View Article : Google Scholar :


Huisman B, Manske G, Carney S and Kalantry S: Functional dissection of the m6A RNA modification. Trends Biochem Sci. 42:85–86. 2017. View Article : Google Scholar : PubMed/NCBI


Yang Y, Hsu PJ, Chen YS and Yang YG: Dynamic transcriptomic m6A decoration: Writers, erasers, readers and functions in RNA metabolism. Cell Res. 28:616–624. 2018. View Article : Google Scholar : PubMed/NCBI


Xu Z, Peng B, Cai Y, Wu G, Huang J, Gao M, Guo G, Zeng S, Gong Z and Yan Y: N6-methyladenosine RNA modification in cancer therapeutic resistance: Current status and perspectives. Biochem Pharmacol. 182:1142582020. View Article : Google Scholar : PubMed/NCBI


Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, Deng X, Wang Y, Weng X, Hu C, et al: R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell. 172:90–105.e23. 2018. View Article : Google Scholar


Zhang J, Tsoi H, Li X, Wang H, Gao J, Wang K, Go MY, Ng SC, Chan FK, Sung JJ and Yu J: Carbonic anhydrase IV inhibits colon cancer development by inhibiting the Wnt signalling pathway through targeting the WTAP-WT1-TBL1 axis. Gut. 65:1482–1493. 2016. View Article : Google Scholar

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Shen S, Guo J, Lv N, Chen Q and Tong J: RNA m6A methylation regulators in endometrial cancer (Review). Int J Oncol 61: 155, 2022
Shen, S., Guo, J., Lv, N., Chen, Q., & Tong, J. (2022). RNA m6A methylation regulators in endometrial cancer (Review). International Journal of Oncology, 61, 155.
Shen, S., Guo, J., Lv, N., Chen, Q., Tong, J."RNA m6A methylation regulators in endometrial cancer (Review)". International Journal of Oncology 61.6 (2022): 155.
Shen, S., Guo, J., Lv, N., Chen, Q., Tong, J."RNA m6A methylation regulators in endometrial cancer (Review)". International Journal of Oncology 61, no. 6 (2022): 155.