Open Access

Functions and mechanisms of N6‑methyladenosine in prostate cancer (Review)

  • Authors:
    • Hongyuan Wan
    • Yanyan Feng
    • Junjie Wu
    • Lijie Zhu
    • Yuanyuan Mi
  • View Affiliations

  • Published online on: July 19, 2022
  • Article Number: 280
  • Copyright: © Wan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Prostate cancer (PCa) has long been a major public health problem affecting men worldwide. Even with treatment, it can develop into castration‑resistant PCa. With the continuous advancement in epigenetics, researchers have explored N6‑methyladenosine (m6A) in search of a more effective and lasting treatment for PCa. m6A is widely distributed in mammalian cells and influences various aspects of mRNA metabolism. Recently, it has been associated with the development or suppression of various types of cancer, including PCa. This review summarizes the recent findings on m6A regulation and its functions and mechanisms in cells, focusing on the various functional proteins operating within m6A in PCa cells. Moreover, the potential clinical value of exploiting m6A modification as an early diagnostic marker in PCa diagnosis and therapeutics was discussed. m6A may also be used as an indicator to evaluate treatment outcome and prognosis.


With an increasing global population and the problems of the aging population, prostate cancer (PCa) has remained a major public health challenge affecting men worldwide (1). It is a highly prevalent malignancy, the second most common cancer, and the leading cause of cancer-related deaths in men, accounting for an estimated 1.6 million cases and 366,000 deaths annually (2).

The high risk of PCa is mainly due to its aggressive metastatic nature. Due to the silent nature of this tumor, early diagnosis and treatment is difficult. In many cases, by the time of diagnosis, the tumor tissue has already developed extraprostatic or even bone metastasis (3,4). The global incidence of PCa has continued to increase in recent years, largely due to increased diagnosis owing to the widespread use of prostate-specific antigen testing; which has allowed the detection of more early-stage cancers. In addition, PCa prevalence increases with age; at present, more than half of Caucasian and Asian men aged >80 years-old have an indolent PCa (5).

PCa is considered a highly heterogeneous cancer characterized by multiple genomic alterations. Accordingly, tumors are graded by clinical hazards ranging from indolent to highly aggressive. Clinicians dealing with PCa patients need to distinguish between PCa and benign prostatic hyperplasia and determine the aggressiveness and metastatic nature of the tumor (1). Hormone therapy, or more accurately, androgen-deficiency treatment (or testosterone therapy), was shown to be effective in the early stages of PCa. However, advanced PCa usually progresses despite androgen ablation, develops castration resistance, and progresses to lethal PCa, which is considered incurable (4,68). Therefore, more effective and lasting treatment for PCa is urgently needed. Currently, proteomics, gene therapy and exosome research, among other approaches are the focus of cancer research. With the recent and growing progress of epigenetics, several researchers have focused on PCa.

N6-methyladenosine (m6A): New hope for PCa

With the advancement in technology for detecting epigenetic modifications, the study of DNA methylation and histone modifications, which are directly linked to tumors, has progressed significantly. Meanwhile, non-coding RNAs have also been increasingly studied (1,911). Consequently, the relationship between RNA modification and PCa was also revealed recently. In particular, the m6A as methylation modification garnered much attention.

m6A is a modification at the sixth position of adenine (A) bases in RNA and occurs in several species (1214). Initially reported in 1974, it did not receive much attention until the detection method was proposed (3). m6A modifications are abundant within the long internal exons, 3′ untranslated (UTR) regions of linear RNAs, and around stop codons. They occur mostly in the RRACH sequence (R=G or A; H=A, C, or U) (15). Similar to other RNA modifications, the m6A modification is regulated by three protein types: methyltransferases, demethylases and binding proteins-more commonly-writers, erasers and readers (16). m6A is involved in various aspects of mRNA metabolism, including mRNA structure, maturation, stabilization, splicing, output, translation and decay. It also affects the cell cycle and differentiation and influences the maintenance of circadian rhythms (17). Besides, m6A can influence tumor occurrence and development via various mechanisms. Furthermore, m6A regulation can affect the progression of cancer and other diseases (1820).

Multiple possibilities: Some mechanisms currently known in PCa databases

The Cancer Genome Atlas and various genomic databases are particularly beneficial for researchers to analyze mRNAs and find targets for characteristic m6A modifications. In previous studies, it was found that approximately all the m6A regulatory factors were associated with androgen receptor (AR), a primary oncogene driver of PCa. Of these regulatory factors, the expression of methyltransferase-like (METTL) 14, fat mass and obesity-associated protein (FTO) and human AlkB homolog H5 (ALKBH5) was reduced, while that of METTL3, YTH domain-containing protein 2 (YTHDC2), YTHDF1, and YTHDF2 was elevated in patients with PCa at different Gleason grades. At advanced pathological stages, the expression levels of Vir-like m6A methyltransferase-associated (VIRMA) and YTHDF3 mRNA were significantly increased (3,21). Recurrence-free survival of PCa was also influenced by IGF2BP3, hnRNP A2/B1, METTL14 and ALKBH5 (22). In AR-dependent and castration-resistant target genes, Somasekharan et al (23) identified that AR mRNA translation is coordinately regulated by the RNA binding proteins YTHDF3 and G3BP1. AR-regulated PCa cell lines subjected to AR pathway inhibition (ARPI) stress showed the recruitment of m6A-modified AR mRNA from actively translating polysomes to RNA-protein stress granules, leading to reduced AR mRNA translation. YTHDF3 or G3BP1 silencing could block ARPI-induced stress granule formation and decrease PCa cell death resulting from ARPI stress (23). However, further research is required to validate these results. A precise understanding of these mechanisms may provide insights into the prevention and treatment of recurrent tumors (2426). In addition, drug development targeting corresponding targets may improve the clinical outcomes of CRPC. Studies focusing on both m6A modification and the tumor immune microenvironment in PCa can lead to more effective immunotherapy approaches (27).

Although database mining resolves several problems, it cannot explain the specific mechanism of m6A methylation in PCa development and progression, especially related molecular mechanisms. Therefore, further experimental exploration is required to determine therapeutic targets for PCa.

Three parts of m6A: Functional proteins and cancer

Collectively, three distinct proteins-readers, writers and erasers-affect cancer development and tumor cell growth. During m6A methylation modification, they cooperate to regulate the position of m6A. They are important targets or components of important pathways in the development of cancer, and should be carefully considered in the field of tumor therapy.


First, we researched the term ‘writers,’ among which, METTL3 is actively being investigated. METTL3 was the first m6A writer identified, followed by other components of the methylation complex, namely, METTL14, METTL4, METTL16, Wilms tumor 1-associating protein (WTAP), KIAA1429/VIRMA, and RNA binding motif protein 15 (RBM15, RBM15B) (3). METTL3/14 is found in the nucleus localized to nuclear speckles. METTL3 and METTL14 are hypothesized to form an m6A-generating heterodimeric enzyme complex on mRNAs, while WTAP functions as the splicing regulator (Fig. 1A) (28). The other writers similarly influence the regulation of m6A modification.

Writers are associated with some altered pathways. In urologic malignancies, the low expression of METTL3 and METTL14 can negatively regulate cell growth-related pathways (mTOR, EMT, and P2XR6) and positively regulate cell death-related pathways or tumor suppressors such as P53, PTEN, and Notch1 (Fig. 1A). Furthermore, METTL3 positively regulated proliferation-related pathways (NK-kB and SHH-GL1) and negatively regulated PTEN (29). The elevated expression of METTL3 in PCa tumor cells promoted the expression of GLI1 in the hedgehog pathway, the growth of PCa, and the motility of cancer cells (30). Similarly, decreased METTL3 expression inhibited LEF1 in the Wnt pathway, thereby preventing tumor cell migration (31). In tumorigenesis, METTL3 was shown to enhance MYC (c-myc) expression by increasing m6A levels of MYC mRNA transcript, triggering PCa (32). Another study revealed that in promoting the proliferation of PCa cells, like YTHDF3, METTL3 could inhibit corresponding mRNA degradation by targeting LHPP and NKX3-1, regulating AKT phosphorylation to induce cancer progression (33).

METTL3 induces m6A modification on Kinesin Family Member 3C (KIF3C) mRNA, promoting the stabilization of KIF3C mRNA by IGF2BP1. Tumor-suppressor factor miR-320d inhibits KIF3C expression by targeting METTL3 and restrains PCa growth, migration and invasion (34). METTL3 mediates m6A modification of ubiquitin-specific peptidase 4 (USP4) mRNA at A2696, and m6A reader protein YTHDF2 binds to and induces the degradation of USP4 mRNA by recruiting RNA-binding protein heterogeneous nuclear ribonucleoprotein D (HNRNPD) to the mRNA. Decreased USP4 levels do not remove the ubiquitin group from ELAV like RNA binding protein 1 (ELAVL1), resulting in a reduction in ELAVL1 protein, which increases Rho GDP dissociation inhibitor alpha (ARHGDIA) expression, promoting the migration and invasion of PCa cells (35). Furthermore, reader proteins and methyltransferase complexes, METTL14 inclusive, can cause poor prognosis by affecting subcellular protein localization (22). Li et al (36) found that METTL3 could enhance the expression of ITGB1 and the adhesion of cancer cells and type I collagen bone matrix, promoting bone metastasis in PCa.

WTAP was shown to affect the development of urinary tumors heterogeneously. It interacted with the Wilms tumor suppressor (WT1) and was also a regulator of the m6A methylation complex, which was responsible for regulating mRNA stability. In addition, binding sites for signal transducer and activator of transcription 1, forkhead box protein O1, interferon regulatory factor 1, glucocorticoid receptor, and peroxisome proliferator-activated receptor γ transcription factor exist in the upstream region of WTAP, which may affect the function of WTAP in tumor formation (37). However, to the best of our knowledge, no detailed reports exist on the mechanism of WTAP action in PCa.


The term ‘erasers’ refers to demethylases and mainly comprises two kinds of proteins-FTO and human ALKBH5. These two proteins regulate m6A modification and render the RNA modification dynamic and reversible (Fig. 1A) (3,16). Increasing evidence suggested that FTO is highly expressed in some types of cancer and is associated with a poor prognosis. However, FTO also acts as a tumor suppressor in thyroid cancer. Low protein expression of FTO was consistent with high tumor grade and increased lymph node metastasis (20). ALKBH5, another m6A demethylase, was shown to either inhibit or promote tumorigenesis. Both FTO and ALKBH5 belong to the AlkB family; the differential recognition and interactions between them and RNA largely result from different conformational outcomes in RNAs, which are induced by m6A. In conclusion, m6A may serve as a conformational marker in regulating the changes in FTO and ALKBH5 expression (38,39).

FTOs are a class of eraser proteins that are downregulated in PCa tissues and cell lines (40). They can downregulate the m6A level and thus inhibit tumor invasion and migration in PCa by regulating total m6A levels (41). For years, FTO mutations rs9939609 and rs9930506 have been reported in the tumor tissues of patients with PCa, and rs9939609 has been negatively associated with overall PCa cases (4244). Li and Cao revealed that FTO could restrain the proliferation, migration and invasion of PCa by downregulating the expression of melanocortin 4 receptor (MC4R) (45). ALKBH5 is also an important reader in cancers, but it remains unexplored in PCa. Studies on m6A erasers are undoubtedly limited to meta-studies, and research on the specific mechanism of FTO and ALKBH5 remains a hot topic.


‘Readers’ include YTH domain-containing protein 1 (YTHDC1), YTHDC2, YTHDF family proteins (YTHDF1, YTHDF2, and YTHDF3), eukaryotic initiation factor 3 (eIF3), heterogeneous nuclear ribonucleoprotein C (hnRNP C), hnRNP A2/B1 and IGF2BP family proteins (IGF2BP1, IGF2BP2 and IGF2BP3) that bind m6A in RNA to regulate the fate of the corresponding RNA and adjust downstream functions (Fig. 1B-D).

The YTH family is divided into the following three major classes: DC1, DC2 and DF (16). They contain an RNA-binding domain, which is a conserved aromatic ring that can recognize the m6A modification (46). YTHDF1 and YTHDF3 can both promote the translation of m6A RNA, while YTHDF2 interferes with the stability of m6A RNA and causes RNA decay. Additionally, YTHDF3 can contribute to mRNA degradation (Fig. 1C and D). By contrast, YTHDC1 is enriched in the nucleus and functions in regulating RNA splicing. Along with the complex functions of YTHDC2, it regulates RNA stability and promotes RNA degradation and translation (47). Furthermore, YTHDC1 modulates mRNA splice site selection in a concentration-dependent manner (Fig. 1B). Another reader, the subunit of eukaryotic initiation factor 3 (eIF3), is closely related to cancer occurrence and development. IGF2BP family proteins recognize and bind the GG(m6A)C sequence via their K homology domains (16). IGF2BP1 (IMP-1)-a non-catalytic post-transcriptional enhancer of tumor growth-is upregulated and associated with adverse prognosis in solid cancers. It shortened the G1 phase of the tumor cells by relying on 3′UTR-, miRNA- and m6A-dependent regulations (48). Like the rest of the family, the overexpression of IGF2BP3 (IMP3) was associated with cancer progression and survival. Using a new RNA sequencing technique, it was found that hnRNPC functioned as an RNA nucleosome in RNA packaging and masking decoy splice (49). While hnRNP A2/B1 was an important cleavage factor, it was an independent prognostic factor, mainly affecting the cell cycle by delaying or promoting cancer progression (50,51). Besides, multiple hnRNP complexes triggered abnormal transcription and splicing of annexin-A7 (ANXA7), a tumor suppressor, thus affecting hnRNP A2/B1 function (52).

Many studies revealed that some readers, including YTHDC1, eIF3f, eIF3S3, and IGF2BP3 (IMP-3), play a corresponding role in influencing PCa progression. Luxton et al found that the oncogene metadherin collocated with YTHDC1 subnuclear spots and regulated the ability of YTHDC1 to affect PCa progression (53). Similarly, the downregulation of eIF3f expression reduces Akt levels, inhibiting PCa growth and progression (54). In some of the earliest studies of advanced PCa, researchers found that upregulated eIF3S3 gene expression was a common phenomenon, suggesting that eIF3S3 overexpression promoted tumor growth (5557). Furthermore, IMP3 was overly altered in tumor tissue, which increased the ubiquitination of PTEN mediated by SMAD-specific E3 ubiquitin-protein ligase 1 (SmurF1) and ultimately activated the PI3K/Akt/mTOR pathway and promoted PCa progression (58).

YTHDF2, eIF3d, EIF3h and IGF2BP1(IMP-1) are all associated with the invasion and proliferation of PCa. YTHDF2 was a direct target of miR-495 and miR-493-3p. In the lysine demethylase 5a (KDM5a)/miRNA-495/YTHDF2/ m6A-MOB3b axis, YTHDF2 recognized the m6A of MOB3b mRNA and induced the degradation of MOB3b mRNA to inhibit its expression. miR-493-3p inhibited the expression of YTHDF2 and thus, increased m6A levels. Thus, high levels of YTHDF2 promoted the proliferation, migration and invasion of PCa cells (59,60). Moreover, eIF3d knockout inhibited the proliferation, invasion and colony formation of tumor cells and arrested the cell cycle in the G2/M phase (61), while EIF3h functions by affecting mRNA translation. High levels of eIF3h directly stimulated protein synthesis and played a key role in establishing and maintaining a malignant state in cells (62). In PCa, 8S-lipoxygenase (8S-LOX) and 15S-LOX-2 inhibited the c-myc mRNA coding region on the determinant-binding protein/insulin-like growth factor-2 mRNA-binding protein 1 (CRD-BP/IMP-1), thereby inhibiting the proliferation of the PCa cell line PC-3 (63).

PCa prognosis was also associated with readers, namely, eIF3b, eIF3c, eIF3L, IGF2BP3 and hnRNP A2/B1. Among them, eIF3b is a strong oncogenic factor and can affect PCa prognosis (64,65), while eIF3c regulates the PI3K/Akt/NF-кB signaling pathway (66). eIF3b silencing leads to a significant increase in tumor suppressor genes PTEN, DIT3 and CDKN1B and a significant decrease in oncogenic genes IRS1 and CDH1 (65). In cancer cells, eIF3b depletion inhibits G1-S cell cycle transformation by altering the expression of cyclin A, cyclin E, retinoblastoma and p27Kip1 proteins, but not RNA. eIF3b depletion also inhibits the migration of cancer cells and destroys their actin cytoskeleton and local adhesions (64). Furthermore, studies showed that androgen-induced eIF3L could facilitate the early diagnosis of PCa disease. A high level of androgen-induced palmitoylation of eIF3L is an obvious marker of PCa. Moreover, as eIF3L acts as an initiation factor, palmitoylated eIF3L may cooperate with the initiation complex and enhance mRNA translation (67), palmitoylated eIF3L can be used to treat castration-resistant PCa (CRPC) (68). Case studies showed that IGF2BP3 was associated with invasive recurrence of tumors, which mainly included extracapsular extension, seminal vesicle invasion, lymphovascular invasion, and a high pathological Gleason score (69). Cheng et al (70) reasoned that hnRNP A2/B1 mainly promoted proliferation, and its high expression in CRPC cells worsens PCa prognosis. Moreover, hnRNP A2/B1 enables CTNNB1 3′-UTR mRNA regulation to alter the expression of β-catenin and other cancer-relevant genes to influence cancer cell phenotypes (71).

Readers can also affect bone metastasis in PCa. Lin et al (72) found that penta-o-galloyl-β-D-glucose, could inhibit the PI3K/Akt/mTOR pathway and reduce epidermal growth factor (EGF) levels to induce the expression of eIF3i and reduce the rate of bone metastasis (72). Moreover, IGF2BP3 was hypothesized to be associated with recurrence and bone metastasis in PCa (73). During PCa metastasis, IGF2BP3 physically binds to circular RNAhsa_circ_0003258 in the cytoplasm to enhance HDAC4 mRNA stability, activate ERK signaling pathway, and trigger EMT programming, ultimately accelerating metastasis (74).

Although the mechanism of some reader proteins remains unexplored, some evidence suggests that reader proteins and their subunits could regulate tumor cell proliferation and development in an m6A-dependent manner, and may be targeted for tumor diagnosis and treatment. For instance, in the IgG reactivity screening of two independent patient cohorts, the response to antigen IgF2BP2 in patients with advanced PCa was higher than that in patients with early PCa, which suggested the possibility of new drug development (75). All of the aforementioned molecular relationships are presented in Table I.

Table I.

Review of the literature regarding m6A modification related proteins, main target and pathway in PCa.

Table I.

Review of the literature regarding m6A modification related proteins, main target and pathway in PCa.

Gene symbolType of enzymeRoleRegulatory factorsMain targetPathwayExpression in cancerImpact in PCa(Refs.)
METTL3WriterOncogene-GLI1HedgehogUpregulatedGrowth and movement(23)
Oncogene-ITGB1-UpregulatedBone metastasis(29)
Oncogene-LHPP, NKX3-1-UpregulatedPromote AKT phosphorylation and progression of cancer(26)
OncogenemiR-320dKIF3C-UpregulatedGrowth, migration and invasion(27)
Oncogene-USP4-UpregulatedMigration and invasion(28)
FTOErasersAnti-oncogene-MC4R-DownregulatedProliferation, migration and invasion(38)
YTHDC1ReaderOncogeneMetadherin--UpregulatedProgression of PCa(46)
YTHDF2ReaderOncogene-LHPP, NKX3-1-UpregulatedPromote AKT phosphorylation and progression of cancer(26)
OncogenemiR-495MOB3b-UpregulatedProliferation, migration and invasion(53)
Oncogene miR-493-3p--UpregulatedProliferation, migration and invasion(52)
eIF3bReaderOncogene---UpregulatedPoor prognosis(57, 58)
eIF3cReaderOncogene--PI3K/Akt/ NF-κbUpregulatedPoor prognosis(59)
eIF3dReaderOncogene---UpregulatedProliferation, invasion, colony formation and down-cell cycle in the G2/M phase(54)
eIF3fReaderOncogene---UpregulatedHigh Akt level and progression of PCa(47)
eIF3hReaderOncogene---UpregulatedMalignant state in cells(55)
eIF3iReaderOncogenePGG-PI3K/Akt/mTORUpregulatedBone metastasis(64)
eIF3LReaderOncogene---UpregulatedPalmitylation to treat CRPC(60)
CRD-BP/IMP-1ReaderOncogene8S-LOX, 15S-LOX-2--UpregulatedProliferation(56)
IGF2BP2ReaderOncogene---UpregulatedAdvance PCa(66)
IGF2BP3ReaderOncogene---UpregulatedProgression, recurrence, metastasis and PCa-specific survival(61,65,73)
Oncogene-SmurF1PI3K/Akt/mTORUpregulatedPTEN ubiquitination, apoptosis inhibition and proliferation(51)
HNRNPA2B1ReaderOncogene---UpregulatedPoor prognosis in CRPC(62)
Oncogene-CTNNB1-UpregulatedHigh stage of tumor(63)
HNRNP complexesReaderOncogene-ANXA7-UpregulatedAffects the function of tumor suppressor factors(45)

[i] GLI1, GLI family zinc finger 1; LEF1, lymphoid enhancer binding factor 1; ITGB1, integrin subunit β1; LHPP, phospholysine phosphohistidine inorganic pyrophosphate phosphatase; NKX3-1, NK3 Homeobox 1; miR-495, microRNA 495; MOB3b, MOB kinase activator 3B; miR-493-3p, microRNA 493-3p; PI3K, phosphoinositide 3-kinase; NF-κb, nuclear factor κB; mTOR, mechanistic target of rapamycin kinase; PTEN, phosphatase and tensin homolog; CTNNB1, catenin β1; CDK19, cyclin-dependent kinase 19.


The risk of PCa-a major long-standing public health problem that affects men worldwide-is mainly due to its aggressive metastatic nature. Castration resistance PCa and advancement to lethal PCa are considered incurable. Understanding the relationship between RNA modification and PCa may lead to the development of new strategies for PCa treatment and thus, m6A modification in the light of PCa is increasingly being studied.

m6A modifications occur in every step of mRNA transcription, splicing, translation and expression; they can systematically change the expression of specific genes and the formation of related proteins. In PCa, many functional groups and regulatory targets show potential as effective treatment. Three types of proteins associated with m6A can equivalently affect the occurrence, development and invasion of cancer. m6A-related mRNAs can be affected by these proteins to modify their expression, which is necessary for the transformation into corresponding oncogenic or tumor-suppressor factors. For PCa treatment, the association between genes and their expressed proteins and corresponding oncogenic or tumor-suppressor factors, including multiple protein pathways and their corresponding targets, have been suggested. Several studies have shown that various m6A-related gene expression changes (whether up- or downregulated) affect PCa prognosis and progression. Therefore, targeted therapies offer great promise (22,76).

However, compared with that of other tumors, the study of m6A in PCa is not comprehensive, and many related protein mechanisms are yet to be explored. Therefore, understanding the precise mechanisms of m6A in PCa, especially PCa-related proteins and genes, may promote the development of more effective cancer treatment. For instance, lysine-specific demethylase 5 (KDM5) family members act as oncogenic drivers in PCa via activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis (59).

The m6A signatures may also serve as an early diagnostic marker to supplement prostate-specific antigen diagnosis, which would improve PCa diagnosis. m6A may also be used as an indicator to evaluate treatment outcome and prognosis follow-up. Although the mechanisms of some gene targets remain unexplored, some writers and readers in m6A have been revealed to promote or inhibit cancer. The development of drugs targeting these targets has great potential for improving PCa treatment.

In summary, the literature on m6A and its mechanism of action in tumors, especially PCa, suggests the rapidly advancing epigenetics approach for cancer treatment, which will benefit patients with PCa.


Not applicable.


The present study was supported by the National Natural Science Foundation (grant nos. 81802576, 81902565 and 81372316), the Jiangsu Provincial Central Administration Bureau (grant no. YB201827), the Wuxi Commission of Health and Family Planning (grant nos. T202024, J202012, Z202011, ZM001, J201802 and J201810), the Science and Technology Development Fund of Wuxi (grant no. WX18IIAN024 and N20202021), the Jiangnan University Wuxi School of Medicine (grant no. 1286010242190070), the Wuxi Taihu Lake Talent Plan, the Supports for Leading Talents in Medical and Health Profession and the Top Talent Support Program for Young and Middle-aged People of Wuxi Health Committee (grant no. BJ2020061).

Availability of data and materials

The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.

Authors' contributions

HYW and YYF were major contributors in writing the manuscript. JJW determined the specific research direction of the manuscript and sorted out the data collected. HYW and JJW created the figure. YYF and JJW performed the literature search. LJZ and YYM made substantial contributions to the design of the manuscript and revised it critically for important intellectual content. All authors have read and approved the final version of the 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.



Sugiura M, Sato H, Kanesaka M, Imamura Y, Sakamoto S, Ichikawa T and Kaneda A: Epigenetic modifications in prostate cancer. Int J Urol. 28:140–149. 2021. View Article : Google Scholar : PubMed/NCBI


Wang G, Zhao D, Spring DJ and DePinho RA: Genetics and biology of prostate cancer. Genes Dev. 32:1105–1140. 2018. View Article : Google Scholar : PubMed/NCBI


Lobo J, Barros-Silva D, Henrique R and Jerónimo C: The emerging role of epitranscriptomics in cancer: Focus on urological tumors. Genes (Basel). 9:5522018. View Article : Google Scholar : PubMed/NCBI


Rebello RJ, Oing C, Knudsen KE, Loeb S, Johnson DC, Reiter RE, Gillessen S, Van der Kwast T and Bristow RG: Prostate cancer. Nat Rev Dis Primers. 7:92021. View Article : Google Scholar : PubMed/NCBI


Kimura T, Sato S, Takahashi H and Egawa S: Global trends of latent prostate cancer in autopsy studies. Cancers (Basel). 13:3592021. View Article : Google Scholar : PubMed/NCBI


Maitland NJ: Resistance to antiandrogens in prostate cancer: Is it inevitable, intrinsic or induced? Cancers (Basel). 13:3272021. View Article : Google Scholar : PubMed/NCBI


Wang Y, Chen J, Wu Z, Ding W, Gao S, Gao Y and Xu C: Mechanisms of enzalutamide resistance in castration-resistant prostate cancer and therapeutic strategies to overcome it. Br J Pharmacol. 178:239–261. 2021. View Article : Google Scholar : PubMed/NCBI


Lowrance WT, Breau RH, Chou R, Chapin BF, Crispino T, Dreicer R, Jarrard DF, Kibel AS, Morgan TM, Morgans AK, et al: Advanced prostate cancer: AUA/ASTRO/SUO guideline PART I. J Urol. 205:14–21. 2021. View Article : Google Scholar : PubMed/NCBI


Borque-Fernando A, Espilez R, Miramar D, Corbatón D, Rodríguez A, Castro E, Mateo J, Rello L, Méndez A and Gil Sanz MJ: Genetic counseling in prostate cancer: How to implement it in daily clinical practice? Actas Urol Esp (Engl Ed). 45:8–20. 2021.(In English, Spanish). View Article : Google Scholar : PubMed/NCBI


Nowacka-Zawisza M and Wiśnik E: DNA methylation and histone modifications as epigenetic regulation in prostate cancer (review). Oncol Rep. 38:2587–2596. 2017. View Article : Google Scholar : PubMed/NCBI


Cimadamore A, Gasparrini S, Scarpelli M, Doria A, Mazzucchelli R, Massari F, Cheng L, Lopez-Beltran A and Montironi R: Epigenetic Modifications and modulators in prostate cancer. Crit Rev Oncog. 22:439–450. 2017. View Article : Google Scholar : PubMed/NCBI


Wang YN, Yu CY and Jin HZ: RNA N(6)-methyladenosine modifications and the immune response. J Immunol Res. 2020:63276142020.PubMed/NCBI


Desrosiers R, Friderici K and Rottman F: Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci USA. 71:3971–3975. 1974. View Article : Google Scholar : PubMed/NCBI


Perry RP, Kelley DE, Friderici K and Rottman F: The methylated constituents of L cell messenger RNA: Evidence for an unusual cluster at the 5′ terminus. Cell. 4:387–394. 1975. 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


Liang Z, Kidwell RL, Deng H and Xie Q: Epigenetic N6-methyladenosine modification of RNA and DNA regulates cancer. Cancer Biol Med. 17:9–19. 2020. View Article : Google Scholar : PubMed/NCBI


Yang Z, Wang T, Wu D, Min Z, Tan J and Yu B: RNA N6-methyladenosine reader IGF2BP3 regulates cell cycle and angiogenesis in colon cancer. J Exp Clin Cancer Res. 39:2032020. View Article : Google Scholar : PubMed/NCBI


Cui H, Wang Y, Li F, He G, Jiang Z, Gang X and Wang G: Quantifying observational evidence for risk of dementia following androgen deprivation therapy for prostate cancer: An updated systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 24:15–23. 2021. View Article : Google Scholar : PubMed/NCBI


Chen X, Xu M, Xu X, Zeng K, Liu X, Pan B, Li C, Sun L, Qin J, Xu T, et al: METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer. Mol Cancer. 19:1062020. View Article : Google Scholar : PubMed/NCBI


Niu Y, Lin Z, Wan A, Chen H, Liang H, Sun L, Wang Y, Li X, Xiong XF, Wei B, et al: RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol Cancer. 18:462019. View Article : Google Scholar : PubMed/NCBI


Wu Q, Xie X, Huang Y, Meng S, Li Y, Wang H and Hu Y: N6-methyladenosine RNA methylation regulators contribute to the progression of prostate cancer. J Cancer. 12:682–692. 2021. View Article : Google Scholar : PubMed/NCBI


Ji G, Huang C, He S, Gong Y, Song G, Li X and Zhou L: Comprehensive analysis of m6A regulators prognostic value in prostate cancer. Aging (Albany NY). 12:14863–14884. 2020. View Article : Google Scholar : PubMed/NCBI


Somasekharan SP, Saxena N, Zhang F, Beraldi E, Huang JN, Gentle C, Fazli L, Thi M, Sorensen PH and Gleave M: Regulation of AR mRNA translation in response to acute AR pathway inhibition. Nucleic Acids Res. 50:1069–1091. 2022. View Article : Google Scholar : PubMed/NCBI


Wood S, Willbanks A and Cheng JX: The role of RNA modifications and RNA-modifying proteins in cancer therapy and drug resistance. Curr Cancer Drug Targets. 21:326–352. 2021. View Article : Google Scholar : PubMed/NCBI


Nombela P, Miguel-López B and Blanco S: The role of m6A, m5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities. Mol Cancer. 20:182021. View Article : Google Scholar : PubMed/NCBI


Barbieri I and Kouzarides T: Role of RNA modifications in cancer. Nat Rev Cancer. 20:303–322. 2020. View Article : Google Scholar : PubMed/NCBI


Liu Z, Zhong J, Zeng J, Duan X, Lu J, Sun X, Liu Q, Liang Y, Lin Z, Zhong W, et al: Characterization of the m6A-Associated tumor immune microenvironment in prostate cancer to aid immunotherapy. Front Immunol. 12:7351702021. View Article : Google Scholar : PubMed/NCBI


Schöller E, Weichmann F, Treiber T, Ringle S, Treiber N, Flatley A, Feederle R, Bruckmann A and Meister G: Interactions, localization, and phosphorylation of the m6A generating METTL3-METTL14-WTAP complex. RNA. 24:499–512. 2018. View Article : Google Scholar : PubMed/NCBI


Tao Z, Zhao Y and Chen X: Role of methyltransferase-like enzyme 3 and methyltransferase-like enzyme 14 in urological cancers. PeerJ. 8:e95892020. View Article : Google Scholar : PubMed/NCBI


Cai J, Yang F, Zhan H, Situ J, Li W, Mao Y and Luo Y: RNA m6A methyltransferase METTL3 promotes the growth of prostate cancer by regulating hedgehog pathway. Onco Targets Ther. 12:9143–9152. 2019. View Article : Google Scholar : PubMed/NCBI


Ma XX, Cao ZG and Zhao SL: m6A methyltransferase METTL3 promotes the progression of prostate cancer via m6A-modified LEF1. Eur Rev Med Pharmacol Sci. 24:3565–3571. 2020.PubMed/NCBI


Yuan Y, Du Y, Wang L and Liu X: The M6A methyltransferase METTL3 promotes the development and progression of prostate carcinoma via mediating MYC methylation. J Cancer. 11:3588–3595. 2020. View Article : Google Scholar : PubMed/NCBI


Li J, Xie H, Ying Y, Chen H, Yan H, He L, Xu M, Xu X, Liang Z, Liu B, et al: YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. Mol Cancer. 19:1522020. View Article : Google Scholar : PubMed/NCBI


Ma H, Zhang F, Zhong Q and Hou J: METTL3-mediated m6A modification of KIF3C-mRNA promotes prostate cancer progression and is negatively regulated by miR-320d. Aging (Albany NY). 13:22332–22344. 2021. View Article : Google Scholar : PubMed/NCBI


Chen Y, Pan C, Wang X, Xu D, Ma Y, Hu J, Chen P, Xiang Z, Rao Q and Han X: Silencing of METTL3 effectively hinders invasion and metastasis of prostate cancer cells. Theranostics. 11:7640–7657. 2021. View Article : Google Scholar : PubMed/NCBI


Li E, Wei B, Wang X and Kang R: METTL3 enhances cell adhesion through stabilizing integrin β1 mRNA via an m6A-HuR-dependent mechanism in prostatic carcinoma. Am J Cancer Res. 10:1012–1025. 2020.PubMed/NCBI


Wu LS, Qian JY, Wang M and Yang H: Identifying the role of Wilms tumor 1 associated protein in cancer prediction using integrative genomic analyses. Mol Med Rep. 14:2823–2831. 2016. View Article : Google Scholar : PubMed/NCBI


Piette ER and Moore JH: Identification of epistatic interactions between the human RNA demethylases FTO and ALKBH5 with gene set enrichment analysis informed by differential methylation. BMC Proc. 12 (Suppl 9):S592018. View Article : Google Scholar


Zou S, Toh JD, Wong KH, Gao YG, Hong W and Woon EC: N(6)-Methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5. Sci Rep. 6:256772016. View Article : Google Scholar : PubMed/NCBI


Wu A, Cremaschi P, Wetterskog D, Conteduca V, Franceschini GM, Kleftogiannis D, Jayaram A, Sandhu S, Wong SQ, Benelli M, et al: Genome-wide plasma DNA methylation features of metastatic prostate cancer. J Clin Invest. 130:1991–2000. 2020. View Article : Google Scholar : PubMed/NCBI


Zhu K, Li Y and Xu Y: The FTO m6A demethylase inhibits the invasion and migration of prostate cancer cells by regulating total m6A levels. Life Sci. 271:1191802021. View Article : Google Scholar : PubMed/NCBI


Lewis SJ, Murad A, Chen L, Davey Smith G, Donovan J, Palmer T, Hamdy F, Neal D, Lane JA, Davis M, et al: Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk. PLoS One. 5:e134852010. View Article : Google Scholar : PubMed/NCBI


Khella MS, Salem AM, Abdel-Rahman O and Saad AS: The association between the FTO rs9939609 variant and malignant pleural mesothelioma risk: A case-control study. Genet Test Mol Biomarkers. 22:79–84. 2018. View Article : Google Scholar : PubMed/NCBI


Salgado-Montilla JL, Rodríguez-Cabán JL, Sánchez-García J, Sánchez-Ortiz R and Irizarry-Ramírez M: Impact of FTO SNPs rs9930506 and rs9939609 in prostate cancer severity in a cohort of puerto rican men. Arch Cancer Res. 5:1482017. View Article : Google Scholar : PubMed/NCBI


Li S and Cao L: Demethyltransferase FTO alpha-ketoglutarate dependent dioxygenase (FTO) regulates the proliferation, migration, invasion and tumor growth of prostate cancer by modulating the expression of melanocortin 4 receptor (MC4R). Bioengineered. 13:5598–5612. 2022. View Article : Google Scholar : PubMed/NCBI


Xu Y, Zhang W, Shen F, Yang X, Liu H, Dai S, Sun X, Huang J and Guo Q: YTH domain proteins: A family of m6A readers in cancer progression. Front Oncol. 11:6295602021. View Article : Google Scholar : PubMed/NCBI


Liu S, Li G, Li Q, Zhang Q, Zhuo L, Chen X, Zhai B, Sui X, Chen K and Xie T: The roles and mechanisms of YTH domain-containing proteins in cancer development and progression. Am J Cancer Res. 10:1068–1084. 2020.PubMed/NCBI


Müller S, Bley N, Busch B, Glaß M, Lederer M, Misiak C, Fuchs T, Wedler A, Haase J, Bertoldo JB, et al: The oncofetal RNA-binding protein IGF2BP1 is a druggable, post-transcriptional super-enhancer of E2F-driven gene expression in cancer. Nucleic Acids Res. 48:8576–8590. 2020. View Article : Google Scholar : PubMed/NCBI


Gruber AJ, Schmidt R, Ghosh S, Martin G, Gruber AR, van Nimwegen E and Zavolan M: Discovery of physiological and cancer-related regulators of 3′ UTR processing with KAPAC. Genome Biol. 19:442018. View Article : Google Scholar : PubMed/NCBI


Jiang M, Lu Y, Duan D, Wang H, Man G, Kang C, Abulimiti K and Li Y: Systematic investigation of mRNA N 6-methyladenosine machinery in primary prostate cancer. Dis Markers. 2020:88334382020. View Article : Google Scholar : PubMed/NCBI


Singh AN and Sharma N: Quantitative SWATH-based proteomic profiling for identification of mechanism-driven diagnostic biomarkers conferring in the progression of metastatic prostate cancer. Front Oncol. 10:4932020. View Article : Google Scholar : PubMed/NCBI


Torosyan Y, Dobi A, Glasman M, Mezhevaya K, Naga S, Huang W, Paweletz C, Leighton X, Pollard HB and Srivastava M: Role of multi-hnRNP nuclear complex in regulation of tumor suppressor ANXA7 in prostate cancer cells. Oncogene. 29:2457–2466. 2010. View Article : Google Scholar : PubMed/NCBI


Luxton HJ, Simpson BS, Mills IG, Brindle NR, Ahmed Z, Stavrinides V, Heavey S, Stamm S and Whitaker HC: The oncogene metadherin interacts with the known splicing proteins YTHDC1, Sam68 and T-STAR and plays a novel role in alternative mRNA splicing. Cancers (Basel). 11:12332019. View Article : Google Scholar : PubMed/NCBI


Li J, Yu W, Ge J, Zhang J, Wang Y, Wang P and Shi G: Targeting eIF3f suppresses the growth of prostate cancer cells by inhibiting Akt signaling. Onco Targets Ther. 13:3739–3750. 2020. View Article : Google Scholar : PubMed/NCBI


Saramäki O, Willi N, Bratt O, Gasser TC, Koivisto P, Nupponen NN, Bubendorf L and Visakorpi T: Amplification of EIF3S3 gene is associated with advanced stage in prostate cancer. Am J Pathol. 159:2089–2094. 2001. View Article : Google Scholar : PubMed/NCBI


Savinainen KJ, Helenius MA, Lehtonen HJ and Visakorpi T: Overexpression of EIF3S3 promotes cancer cell growth. Prostate. 66:1144–1150. 2006. View Article : Google Scholar : PubMed/NCBI


Savinainen KJ, Linja MJ, Saramäki OR, Tammela TL, Chang GT, Brinkmann AO and Visakorpi T: Expression and copy number analysis of TRPS1, EIF3S3 and MYC genes in breast and prostate cancer. Br J Cancer. 90:1041–1046. 2004. View Article : Google Scholar : PubMed/NCBI


Zhang X, Wang D, Liu B, Jin X, Wang X, Pan J, Tu W and Shao Y: IMP3 accelerates the progression of prostate cancer through inhibiting PTEN expression in a SMURF1-dependent way. J Exp Clin Cancer Res. 39:1902020. View Article : Google Scholar : PubMed/NCBI


Du C, Lv C, Feng Y and Yu S: Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression. J Exp Clin Cancer Res. 39:2232020. View Article : Google Scholar : PubMed/NCBI


Li J, Meng S, Xu M, Wang S, He L, Xu X, Wang X and Xie L: Downregulation of N6-methyladenosine binding YTHDF2 protein mediated by miR-493-3p suppresses prostate cancer by elevating N6-methyladenosine levels. Oncotarget. 9:3752–3764. 2018. View Article : Google Scholar : PubMed/NCBI


Gao Y, Teng J, Hong Y, Qu F, Ren J, Li L, Pan X, Chen L, Yin L, Xu D and Cui X: The oncogenic role of EIF3D is associated with increased cell cycle progression and motility in prostate cancer. Med Oncol. 32:5182015. View Article : Google Scholar : PubMed/NCBI


Zhang L, Smit-McBride Z, Pan X, Rheinhardt J and Hershey JW: An oncogenic role for the phosphorylated h-subunit of human translation initiation factor eIF3. J Biol Chem. 283:24047–24060. 2008. View Article : Google Scholar : PubMed/NCBI


Kawakami Y, Kubota N, Ekuni N, Suzuki-Yamamoto T, Kimoto M, Yamashita H, Tsuji H, Yoshimoto T, Jisaka M, Tanaka J, et al: Tumor-suppressive lipoxygenases inhibit the expression of c-myc mRNA coding region determinant-binding protein/insulin-like growth factor II mRNA-binding protein 1 in human prostate carcinoma PC-3 cells. Biosci Biotechnol Biochem. 73:1811–1817. 2009. View Article : Google Scholar : PubMed/NCBI


Wang H, Ru Y, Sanchez-Carbayo M, Wang X, Kieft JS and Theodorescu D: Translation initiation factor eIF3b expression in human cancer and its role in tumor growth and lung colonization. Clin Cancer Res. 19:2850–2860. 2013. View Article : Google Scholar : PubMed/NCBI


Xiang P, Sun Y, Fang Z, Yan K and Fan Y: Eukaryotic translation initiation factor 3 subunit b is a novel oncogenic factor in prostate cancer. Mamm Genome. 31:197–204. 2020. View Article : Google Scholar : PubMed/NCBI


Hu J, Luo H, Xu Y, Luo G, Xu S, Zhu J, Song D, Sun Z and Kuang Y: The prognostic significance of EIF3C gene during the tumorigenesis of prostate cancer. Cancer Invest. 37:199–208. 2019. View Article : Google Scholar : PubMed/NCBI


Hershey JW: The role of eIF3 and its individual subunits in cancer. Biochim Biophys Acta. 1849:792–800. 2015. View Article : Google Scholar : PubMed/NCBI


Cui L, Liu M, Lai S, Hou H, Diao T, Zhang D, Wang M, Zhang Y and Wang J: Androgen upregulates the palmitoylation of eIF3L in human prostate LNCaP cells. Onco Targets Ther. 12:4451–4459. 2019. View Article : Google Scholar : PubMed/NCBI


Chromecki TF, Cha EK, Pummer K, Scherr DS, Tewari AK, Sun M, Fajkovic H, Roehrborn CG, Ashfaq R, Karakiewicz PI and Shariat SF: Prognostic value of insulin-like growth factor II mRNA binding protein 3 in patients treated with radical prostatectomy. BJU Int. 110:63–68. 2012. View Article : Google Scholar : PubMed/NCBI


Cheng Y, Li L, Qin Z, Li X and Qi F: Identification of castration-resistant prostate cancer-related hub genes using weighted gene co-expression network analysis. J Cell Mol Med. 24:8006–8017. 2020. View Article : Google Scholar : PubMed/NCBI


Stockley J, Villasevil ME, Nixon C, Ahmad I, Leung HY and Rajan P: The RNA-binding protein hnRNPA2 regulates β-catenin protein expression and is overexpressed in prostate cancer. RNA Biol. 11:755–765. 2014. View Article : Google Scholar : PubMed/NCBI


Lin VC, Kuo PT, Lin YC, Chen Y, Hseu YC, Yang HL, Kao JY, Ho CT and Way TD: Penta-O-galloyl-β-D-glucose suppresses EGF-induced eIF3i expression through inhibition of the PI3K/AKT/mTOR pathway in prostate cancer cells. J Agric Food Chem. 62:8990–8996. 2014. View Article : Google Scholar : PubMed/NCBI


Xie C, Li Y, Li Q, Chen Y, Yao J, Yin G, Bi Q, O'Keefe RJ, Schwarz EM and Tyler W: Increased insulin mRNA binding protein-3 expression correlates with vascular enhancement of renal cell carcinoma by intravenous contrast-CT and is associated with bone metastasis. J Bone Oncol. 4:69–76. 2015. View Article : Google Scholar : PubMed/NCBI


Yu YZ, Lv DJ, Wang C, Song XL, Xie T, Wang T, Li ZM, Guo JD, Fu DJ, Li KJ, et al: Hsa_circ_0003258 promotes prostate cancer metastasis by complexing with IGF2BP3 and sponging miR-653-5p. Mol Cancer. 21:122022. View Article : Google Scholar : PubMed/NCBI


Pin E, Henjes F, Hong MG, Wiklund F, Magnusson P, Bjartell A, Uhlén M, Nilsson P and Schwenk JM: Identification of a novel autoimmune peptide epitope of prostein in prostate cancer. J Proteome Res. 16:204–216. 2017. View Article : Google Scholar : PubMed/NCBI


Wang J, Lin H, Zhou M, Xiang Q, Deng Y, Luo L, Liu Y, Zhu Z and Zhao Z: The m6A methylation regulator-based signature for predicting the prognosis of prostate cancer. Future Oncol. 16:2421–2432. 2020. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

Volume 26 Issue 3

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
Spandidos Publications style
Wan H, Feng Y, Wu J, Zhu L and Mi Y: Functions and mechanisms of N6‑methyladenosine in prostate cancer (Review). Mol Med Rep 26: 280, 2022
Wan, H., Feng, Y., Wu, J., Zhu, L., & Mi, Y. (2022). Functions and mechanisms of N6‑methyladenosine in prostate cancer (Review). Molecular Medicine Reports, 26, 280.
Wan, H., Feng, Y., Wu, J., Zhu, L., Mi, Y."Functions and mechanisms of N6‑methyladenosine in prostate cancer (Review)". Molecular Medicine Reports 26.3 (2022): 280.
Wan, H., Feng, Y., Wu, J., Zhu, L., Mi, Y."Functions and mechanisms of N6‑methyladenosine in prostate cancer (Review)". Molecular Medicine Reports 26, no. 3 (2022): 280.