M⁶A refers to the methylation modification of the sixth nitrogen atom of adenine (45). As an epigenetic marker that acts primarily on RNA, m⁶A methylation modification relies on the m⁶A methyl-conversion enzyme. It has been demonstrated that m⁶A methyltransferases consist of a catalytic subunit m⁶A-METTL complex and a regulatory subunit m⁶A-METTL associated complex, also known as a ‘writer’ (46). The m⁶A methyltransferase complex consists of two protein substances, METTL3 and METTL14, and contains WTAP, KIAA1429 (Virilizer), Hakai, RNA binding motif protein 15 (RBM15), METTL16 and additional co-regulatory subunits (45,47). The METTL3-METTL14 complex exhibits more potent in vitro methyltransferase activity than any single protein. Thus, METTL3 and METTL14 are the core components of the m⁶A writer complex. Although METTL14 lacks the catalytic activity of methyltransferase and is a pseudo methyltransferase in the complex, it plays an integral role in maintaining the activity of the writer complex. METTL14 plays an essential role in maintaining the structural integrity of the binary complex of METTL3-METTL14 complex to improve the catalytic activity of the m⁶A writer complex. Recombinant METTL3 monomers exhibit weak methyltransferase catalytic activity. METTL3 exhibits a significant increase in methyltransferase catalytic activity when METTL3 and METTL14 with methyltransferase domains form heterodimeric complexes (48). WTAP has a unique localization role in recruiting METTL3 and METTL14 into the nuclear spot. In addition, WTAP participates in the m⁶A methylation modification process as part of the m⁶A methyltransferase complex, along with METTL3, METTL14, and other methyltransferases (49). RBM15, as a member of a family of adapter proteins that contain RNA binding motifs, primarily recruits m⁶A methylated RNA into U-rich regions (50). Vir like m⁶A methyltransferase associated (Virma), also known as KIAA1429, recruits the WTAP-METTL3-METTL14 complex by binding to WTAP. Alternatively, Virma may interact with plant cleavage factors linked to m⁶A methylation and polyadenylation mechanisms, participating in mRNA processing (51). METTL5 is an 18srRNA m⁶A methyltransferase that acquires metabolic stability by forming parallel β zippers between the backbone atoms and heterodimers with the tRNA methyltransferase homolog 112. METTL16 can directly methylate mRNA containing the UAC m⁶A GAGAA motif (52). Zinc refers to the CCCH domain-containing protein 13 (ZC3H13) and E3 ubiquitin-protein ligase Hakai, which interacts with the methyltransferase complex to affect the RNA methylation process (48) (Table I).

Thus far, only two types of m⁶A demethylase have been identified: FTO and ALKBH5. FTO, also known as ALKBH9, belongs to the non-heme KGFe(II)/α-KG-dependent family of dioxygenase ALKB (ABH1-9) and is the m⁶A demethylase of the first eukaryotic mRNA enzyme. The role of FTO in adipogenesis and tumorigenesis is related to its m⁶A demethylase activity. It can also interact with melanocortin receptor 4 (MC4R) through m⁶A modification to control the proliferation, migration, and the invasion of PCa cells (53).

FTO has been reported to play a key role as a demethylase in a various types of cancer. FTO is responsible for the dynamic modification of m⁶A and mediates m⁶A and the N6,2-O-dimethyladenosine (m⁶Am) demethylation of poly(A) RNA. The demethylation of m⁶A is first mediated when FTO is in the nucleus, and demethylation of m⁶A and m⁶Am is first mediated when FTO is in the cytoplasm. FTO demethylase promotes abnormal m⁶A modification in PCa. This suggests that FTO has a tumor-suppressing effect in PCa (54). In addition, FTO depletion first significantly increases the m⁶A levels of chloride intracellular channel protein 4 (CLIC4) mRNA, and subsequently inhibits PCa proliferation and transfer by reducing mRNA stability and promoting CLIC4 mRNA degradation (55).

ALKBH5, by removing m⁶A methylation, leads to the erasure of m⁶A methylation modifications, returning m⁶A to its previously unregulated state. Of note, seven m⁶A-associated crosstalk genes, including ALKBH5, are differently expressed in PCa and periodontitis. These genes have significantly increased expression levels in several signaling pathways, including nuclear plasticity transport, ubiquitin-mediated protein breakdown, p53 signal transduction, cellular senescence, and transcriptional regulation disorders (56). The expression of the ALKBH5 gene with abnormal copy number changes is strongly associated with the prognosis of PCa (57). This suggests that the pattern of ALKBH5 copy number variation is significantly associated with relapse-free survival in PCa (56). Furthermore, it has been found that FTO and ALKBH5 are negatively associated with the Gleason grade and are less well expressed in PCa (58). The abnormal expression of FTO or ALKBH5 primarily affects m⁶A levels, which then, through complex biological mechanisms, affect certain biological processes of tumorigenesis and development (Table II).

M⁶A methylation modifications perform their corresponding biological functions with the involvement of the writer and eraser and with the recognition of m⁶A modifications by m⁶A recognition proteins. IYT521-B homologous (YTH) family proteins were the first m⁶A reader proteins to be discovered. It was found that m⁶A readers are primarily involved in the occurrence and development of cancer by regulating the metabolism of targeted RNA, including RNA splicing, output, translation and degradation, which result in changes in the biological function of RNA. At present, a total of five proteins containing the YTH domain in the human genome have been found and divided into three types of m⁶A reader proteins: YTH m⁶A-binding protein 1–3 (YTHDF1-3), YTH domain 1 (YTHDC1) and YTH domain 2 (YTHDC2) (59).

The degradation of mRNA and tje translation of YTH family members, with different reader proteins, play their respective roles through different pathways. YTHDF1 may recruit argonaute 2 protein and miRNA via the YTH domain and interact to form P-body (mRNA degradation centers in yeast cells and animal cells, also known as cytoplasmic bodies, Dcp bodies, or GW bodies) to degrade mRNA. Moreover, YTHDF1 facilitates the translation of m⁶A-modified mRNA (10,60). In addition, YTHDF1 recognizes m⁶A-modified target genes through multiple mechanisms. Thus, YTHDF1 improves the stability of RNA and thus promotes expression (61). YTHDF2 relies primarily on m⁶A modifications to regulate signaling pathways in cancer cells. YTHDF2 promotes the degradation of targeted mRNA transcripts by recruiting the CCR4-NOT deadenylase complex. YTHDF2 can also promote tumor cell proliferation by binding to tumor suppressors, triggering a downstream cascade that can do the opposite by interacting with oncogenes (62). YTHDF2 also affects various aspects of RNA metabolism, including mRNA degradation and ribosome pre-RNA processing (10). The YTHDF family protein DF1-3 is the dominant cytosolic m⁶A-binding protein and is considered to mediate the action of m⁶A in cells. All three DF proteins contribute to the destabilization of mRNA and together, mediate the degradation of mRNAs containing m⁶A (63). YTHDF3 functions synergistically with YTHDF1 to promote protein synthesis and mediates the decay of methylated mRNA by affecting YTHDF2. YTHDF1-3 cooperates and plays a crucial role in facilitating the metabolism of m⁶A-modified mRNA in the cytoplasm (64). YTHDC1 is also the only m⁶A reader in the YTH protein family that is localized in the nucleus. YTHDC1 is a protein that interacts with splicing factors that regulate RNA splicing. Its m⁶A-dependent functions include selective polyadenylation and the nuclear production of m⁶A-modified mRNAs, which control the maturation of intranuclear mRNA. Recent research has demonstrated that there is a close association between chromatin-associated RNAs, non-coding RNAs, and regulatory RNAs, which can control the expression of genes within cells (65). It has been shown that YTHDC1 plays a crucial role in cellular functions, such as cancer cell proliferation. YTHDC1 may also have the potential to promote the efficacy of tumor immunotherapy (66). YTHDC2 plays its biological role in using its distinct RNA binding domain to bind to targeted m⁶A RNA and bridge between ribosomes, which reduces the abundance of related mRNAs and increases the translation efficiency of related mRNAs (67,68).

The reader protein includes not only the YTH structural protein family, but also the heterogeneous nuclear ribonucleoprotein protein (HNRNP) family and IGF2BP1, IGF2BP2, and IGF2BP3. The HNRNP family and IGF2BP1-3 together recognize m⁶A-modified fragments in RNA (69). HNRNPC is regulated as an m⁶A switch, which affects the abundance and selective splicing of target RNAs by altering their binding activity. HNRNPC can also facilitate the conversion of fresh heteronuclear RNAs into mature mRNAs, and can stabilize the structure of mRNAs and control their translation process (70). The RGG motif of HNRNPG directly binds to the phosphorylated carboxyl terminal domain of RNA polymerase II (RNAPII). The interaction between the phosphorylated carboxyl terminal domain and the new RNA leads to the co-transcription of HNRNPG and RNAPII. Finally, selective splicing of new RNA (71). HNRNPA2B1 specifically recognizes and directly binds with elevated affinity to RNAs that share the m⁶A-modified RNAs containing the m⁶A co-sequence RGm⁶ACH. M⁶A can boost the binding capability of HNRNPA2B1 to certain sites, which enhances its nuclear event capability. In addition, HNRNPA2B1 recruits the microprocessor complexes, Drosha and DGCR8, to facilitate primary miRNA processing by binding m⁶A to primary miRNA transcripts (72). IGF2BPs first identify m⁶A-modified mRNA and improve the stability of the mRNA target which facilitates storage, translation, and gene expression output. IGF2BPs may exert oncogenic effects on cancer cells by enhancing the stability of methylated mRNAs of oncogenic targets (73,74) (Table III).

Recent research has demonstrated that chemotherapeutic resistance in cancer is associated with m⁶A RNA methylation, which leads to the abnormal expression of various targets and pathways. For example, the resistance of lung adenocarcinoma to the clinically used drugs nicotine and oseltamivir is due to an increase in MET-TL7B content in the cancer tissue, which enables m⁶A expression and reactive oxygen species (ROS) clearance dependence (75). The development of resistance to gefitinib in lung adenocarcinoma has also been found to be associated with the ribonucleic acid cleavage of m⁶A-modified circASK1 produced by YTHDF2 (76). Resistance to the chemotherapeutic drug, cisplatin, in esophageal squamous epithelial carcinoma has also been found to be associated with m⁶A. The stability of the CASC8 transcription process is enhanced by the m⁶A demethylation induced by ALKBH5, which induces drug resistance in esophageal squamous epithelial carcinoma (77). In addition, resistance to cisplatin in intrahepatic cholangiocarcinoma promotes the degradation of CDKN1B mRNA via YTHDF2 in an m⁶A-dependent manner (78). Tamoxifen is a conventional chemotherapy drug for breast cancer (79). Breast cancer develops tamoxifen resistance due to an increased ROS production and p38 activation. One of the reasons for this mechanism is that AK4mRNA translation is enhanced by METTL3-mediated m⁶A overexpression (80). HNRNPA2B1 activates the ser/thr kinase growth factor signaling pathway in an m⁶A-dependent manner to abnormally regulate downstream targets, leading to tamoxifen resistance in cancer tissue. Resistance to temozolomide in glioblastoma multiforme arises from the transcription of histone-associated genes modified by METTL3-mediated m⁶A (81). Strong resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma is regulated by the YTHDC1-mediated m⁶A-dependent YTHDC1/ANXA1 axis (82). In addition, the decreased sensitivity of PCa to enzalutamide is due to the methylation of nuclear receptor subfamily 5 group A member 2 (NR5A2), which is caused by the low expression of METTL3 (83). The mechanism of m⁶A development and enhancement of cancer resistance is receiving increasing attention, which provides insight for future drug development and potential therapeutic targets which can be used to reduce resistance.

It has been shown that an increased expression of METTL3 may have a tumor-promoting effect (85). Increased expression levels of METTL3 can promote the proliferation, migration and invasion of PCa by promoting ARHGDIA expression, and leading to an upregulation of the total m⁶A methylation modification level in PCa tissue (86). In addition, the overexpression of METTL3 increases the m⁶A content, and promotes the growth and invasion of PCa cells through Sonic hedgehog (SHH)-GLI family zinc finger 1 (GLI1) signaling (87). The m⁶A methylation of lymphoid enhancer-binding factor 1 mRNA is mediated by METTL3. Lymphoid enhancer-binding factor 1 enhances the activity of the Wnt/β-catenin pathway, promotes the proliferation of prostate cancer cells and inhibits cell differentiation (88). METTL3 promotes the maturation of pre-miRNAs by upregulating the m⁶A content and interacting with the microprocessor protein, DGCR8, to mediate m⁶A modification, which recognizes pre-miR-182 (89). The m⁶A modification of the METTL3-mediated long non-coding RNA (lncRNA) MALAT1 can also promote PCa cell growth and transfer by activating PI3K/AKT signaling (90). METTL3 increases the m⁶A level of MYC mRNA transcription and enhances MYC expression, which leads to the occurrence and development of PCa (91). METTL3 can also induce m⁶A modification on kinesin superfamily protein 3C (KIF3C) by increasing the stability of IGF2-binding protein 1 to KIF3C-mRNA. KIF3C is overexpressed in PCa, which promotes its growth, migration and invasion during the m⁶A-dependent miR-320d/METTL3 (92). The tiny lipid molecule, lipoxin A4, in PCa cells promotes the polarization of M2-like macrophages by inhibiting the METTL3-medidated activation of STAT6, which produces effects that enhance tumor metastasis and growth activity. M⁶A levels were reduced in tumor-associated macrophages in PCa patients. METTL3 drives M1 macrophage polarization through the methylation of STAT1 mRNA, which exerts antitumor effects (93). METTL3 levels in patients with PCa are up-regulated, promoting cell proliferation, migration and invasion in PCa via a variety of mechanisms (Fig. 2).

WTAP is a writer for m⁶A methylation modification in PCa tissue (58). In PCa, WTAP has been shown to promote cell proliferation and metastasis by binding to the corresponding androgen receptor. STAT1, FOXO1, Interferon regulatory factor 1, glucocorticoid receptor and PPARγ transcription factor binding sites were identified in the promoter region of the WTAP gene. WTAP expression may be affected by these tumor-associated transcripts to promote tumorigenesis (94). WTAP may play a role in the processing of androgen-responsive circular RNA (circRNA) biogenesis. circRNAs can be used as non-invasive markers for PCa diagnosis and prognosis (95).

A lack of FTO attenuates growth rates and elevated levels of FTO expression can lead to weight gain due to an increased energy intake; FTO was first identified as a gene associated with weight and obesity. It has been shown that FTO can function as an eraser of m⁶A methylation modifications, which manipulate m⁶A methylation reversals and participate in dynamically reversible m⁶A modifications (54). It was found that FTO is downregulated in PCa. FTO and ALKBH5 are inversely correlated with the Gleason classification of PCa (58). It has been suggested that FTO is an oncogene in PCa (96). FTO m⁶A demethylase inhibits the invasion and migration of PCa cells by regulating total m⁶A levels. When FTO is present in the nucleus, it first promotes the demethylation of m⁶A. It first promotes the demethylation of m⁶A and m⁶Am when FTO is present in the cytosol. It has been shown that FTO in PCa cells is primarily found in the nucleus. mRNA decay experiments have also shown that the knockout of FTO does not affect the stability of the target mRNA in PCa cell lines. Increased levels of FTO expression may be associated with obesity-associated FTO single nucleotide polymorphisms, and promote tumorigenesis and progression (54). In addition, the m⁶A modification is positively associated with the degree of tumor malignancy, which suggests a tumor suppressor effect of FTO in PCa (54).

It has been shown that FTO can also affect the occurrence and development of PCa by modulating the MC4R content. It promotes mRNA stability and modulates nuclear processes, miRNA processing and retinol-binding protein interactions. FTO is capable of oxidizing single-stranded DNA and single-stranded RNA in vitro to demethylate m-3T and m-3U. Moreover, the FTO and MC4R expression levels exhibit a significant negative correlation. The high expression of FTO partially modifies the boosting effect of high MC4R expression on the PCa malignant phenotype (53).

In addition, CLIC4 is one of the functional targets of FTO-mediated m⁶A modification by multiple assays. FTO depletion suppresses PCa proliferation and transfer by increasing m⁶A levels of CLIC4 mRNA which decreases mRNA stability. Functionally, FTO inhibits PCa cell proliferation and metastasis in vitro and in vivo, which are associated with a poor prognosis of patients with PCa, while the ectopic expression of FTO has the opposite effect (55).

The polymorphisms rs9930506 and rs9939609 in the FTO gene have been found to be associated with obesity and PCa (97). Both rs9930506 and rs9939609 are associated with high BMI in the European population, while obesity is associated with a high risk of developing PCa, which suggests an association between FTO genotypes and the risk of developing PCa. The mutation of rs9939609 is negatively associated with the risk of developing PCa and is positively associated with being overweight. Cases of severe PCa are more likely to occur in individuals who are overweight and have a mutation in the rs9939609 gene. The prevalence of heterozygous forms of rs9939609 suggests that its ‘A’ allele may be related to the phenotype of PCa (97). The rs9939609 A allele has been found to be associated with cancer risk in PCa cases, which is not with the occurrence of an increased risk of PCa itself. The data suggest that the rs9939609 A allele reduces PCa risk and the likelihood of detecting low-grade PCa, which may increase the likelihood of elevated-grade PCa (98). In addition, it has been suggested that FTO rs8050136 polymorphisms are not associated with PCa (97,99).

ALKBH5 is a member of the m⁶A ‘eraser’, which functions as a demethylase. In model-based studies, ALKBH5 has been shown to affect PCa diagnosis and prognosis. Lower levels of ALKBH5 reduce protein expression in the tumor. It has been suggested that a reduction in the ALKBH5 level, which is caused by the deletion of the ALKBH5 amplification gene, is a factor in the development and progression of PCa (57). The expression of ALKBH5 has been shown to be significantly increased in patients with PCa compared to the normal population. Patients with CRPC with bone metastases have been found to have higher levels of ALKBH5 than patients with CRPC with lymph node metastases. Furthermore, ALKBH5 is negatively associated with the Gleason score, which suggests that ALKBH5 may be an indicator of PCa prognosis (56,58). The differential methylation of the ALKBH5 CpG site may enhance the progression of PCa transfer, although the specific molecular mechanisms remain unknown (100).

YTHDF2 and METTL3 have been found to be expressed at increased levels in PCa, which suggests a lower overall survival. The in vitro and in vivo inhibition of YTHDF2 and METTL3 has been shown to inhibit PCa development. This suggests an association between YTHDF2/METTL3 and PCa (101). YTHDF2 is overexpressed in PCa and CRPC with lymph node metastasis and is positively associated with the Gleason grade in PCa (58). The C and N terminal domains of YTHDF2 play the roles of specifically binding to the m⁶A modification site, recruiting the CCR4-NOT complex and mediating the localization of the YTHDF2mRNA complex to the cellular RNA decay site, respectively. METTL3 functions as a core writer-catalyzed m⁶A modification, which can promote YTHDF2 to play a regulatory role. YTHDF2 can directly bind to the m⁶A modification sites of NK3 homeobox 1 (NKX3-1) and phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP), and degrade their mRNA, which indirectly induces AKT phosphorylation modification and promotes PCa occurrence and development in an m⁶A-dependent manner. The increased expression of NKX3-1 suppresses the development of PCa, while LHPP suppresses AKT phosphorylation modification to regulate tumor progression (56,101). In addition, YTHDF2 is a target gene for miR-495 and is negatively associated with it. miR-495 can bind to the mRNA of YTHDF2. The knockout of miR-495 has been shown to significantly reduce cell proliferation and transfer in the DU-145 and PC3 PCa cell lines. YTHDF2 overexpression attenuates the inhibitory effect of miR-495 on PCa development and induces apoptotic effects (102). In addition, as previously demonstrated, YTHDF2 can recruit the RNA-binding protein HNRNPD and bind to ubiquitin specific protease 4 (USP4) mRNA, which induces mRNA degradation. The reduction in the USP4 level fails to remove the ubiquitin group in the ELAVL1 protein, which results in a reduction in the ELAVL1 protein content. It allows ARHGDIA to be over-expressed and promotes PCa development (86). In addition, the expression levels of YTHDF2 are increased in PCa tissue and in the DU-145 and PC3 cell lines, while miR-493-3p expression is decreased, suggesting an inverse correlation (103). The target protein of miR-493-3p is YTHDF2, which is also an upstream factor in the inhibition of PCa cell line development by YTHDF2. The overexpression of miR-493-3p leads to an increase in m⁶A levels, while the inhibition of miR-493-3p leads to a decrease in m⁶A levels. The miR-493-3p-mediated downregulation of YTHDF2 significantly suppresses PCa progression by increasing the m⁶A levels. YTHDF2 and miR-493-3p indirectly alter the occurrence and development of PCa in an m⁶A-dependent manner (103).

It has been shown that the IGF2BP1 protein family primarily acts as a recognition enzyme for m⁶A methylation modification and as a cancer promoter. METTL3 induces an increase in the level of m⁶A methylation modification of KIF3C, improving the stability of IGF2BP1 against KIF3C mRNA and reducing KIF3C mRNA degradation. KIF3C is expressed at peak levels in PCa tissues and cell lines, which is positively associated with PCa growth, migration and invasion. Following the knockdown if METLL3, the expression of m⁶A and KIF3C is reduced. The expression and stability of KIF3C are reduced following the knockout of IGF2BP1. Thus, IGFBP1 positively modulates the stability and expression of KIF3C by relying on m⁶A (92).

It has been shown that METTL14 facilitates the occurrence and development of PCa in vitro and in vivo. METTL14 recruits the YTHDF2 protein in an m⁶A-dependent manner to inhibit thrombospondin 1 (THBS1) mRNA expression (104). METTL14 methylates the THBS1 mRNA in an m⁶A-dependent manner. Methylated THBS1 mRNA can be recognized by the YTHDF2 protein which binds to the m⁶A site in the cytoplasm leading to the degradation of the THBS1 mRNA. In addition, METTL14 can inhibit the angiogenesis inhibitory effect of THBS1 in an m⁶A-dependent manner, which provides sufficient energy and oxygen for the growth of PCa tissues and cell lines (104).

In addition, increased METTL14 and ZC3H13 expression levels are positively associated with the number of Th1 cells and Th17 cells, as well as with the mesenchymal fraction and transforming growth factor-β responses. An increased mesenchymal fraction of Th1 cell and Th17 cell numbers suggests a good prognosis in PCa (105).

The expression of KIA1429 and HNRPA2B1 leads to m⁶A methylation modification, which indicates a poor prognosis in PCa. This will lead to increased intracellular heterogeneity and Th2 cell penetration within PCa tissues and cell lines, with lower Th17 cell penetration and macrophage M1/M2 polarization (105).

The overexpression of Virma leads to increased levels of m⁶A RNA methylation in androgen-independent PCa cells and CRPCs. It has been shown that the viability and proliferation of PC-3 cells can be suppressed by Virma inhibition. The downregulation of Virma attenuates PCa migration and aggressiveness by inhibiting m⁶A expression, which decreases the stability and abundance of lncRNA, and reduces the malignant phenotype of PCa (106).

The expression levels of YTHDC2 and YTHDF1 are elevated in PCa and CRPC with lymphoma metastases, suggesting a poor prognosis (58). In addition, YTHDF1 overexpression induces the occurrence and development of PCa. It has been shown that the downstream factor of YTHDF1 is polo-related kinase1 (PLK1). YTHDF1 recognizes PLK1 mRNA and interacts with the m⁶A modification of PLK1 mRNA 3′ non-coding region in an m⁶A modification-dependent manner, which improves the translation efficiency of PLK1 mRNA and increases the level of PLK1. It can promote the activation of the PI3K/AKT signaling pathway. Finally, YTHDF1 promotes the occurrence and development of PCa by increasing the PLK1 protein content and activating the PI3K/AKT signaling pathway (107).

HNRNPA2B1 promotes the genesis and development of PCa tissue in an m⁶A-dependent manner, including several nuclear processes (108). In addition, HNRNPA2B1 has been shown to be associated with recurrence-free survival in PCa, which suggests its association with a poor prognosis (96). HNRNPA2B1 can also enhance its expression levels through lncRNA-PCAT6 (PCAT6), which promotes the occurrence and development of PCa. The knockout of the hnRNPA2B1 gene significantly reduces the ability of PCa cells to grow and migrate due to PCAT6 (109).

The HNRNPC protein can enhance the stability of the nucleosome assembly protein (NAP1) L2 mRNA by binding to lncNAP1L6, which is recruited into the m⁶A-methylated modified NAP1L2 mRNA. HNRNPC indirectly promotes the increase of NAP1L2 in NAP1L2 translational expression products, and induces PCa transfer and invasion by the activation of the MMP signaling pathway (110).

The protein IGF2BP2 recognizes m⁶A-methylated PCAT6 and enhances RNA stability, which shortens the half-life of PCAT6. PCAT6 is overexpressed in PCa tissues with bone metastases and is associated with the poor prognosis of patients with PCa (111).

IGF2BP3 binds to hsa_circ_0003258 and enhances the stability of the HDAC4 mRNA, which activates the ERK signaling pathway and accelerates the transfer and invasion of PCa tissue (112).

In the process of PCa, multiple m⁶A regulators are required to participate in regulation. Each regulator is interconnected or mutually restricted and jointly regulates the body's m⁶A levels. The complex and diverse regulatory mechanisms make it difficult to study the association between m⁶A and PCa.

METTL3 plays a direct role in AR expression. The knockdown of METTL3 leads to the increased expression of the AR target gene, NKX3.1, and to the decreased expression of PSA. The knockdown of METTL3 leads to an increase in the key regulatory factor lysine-specific demethylase-1. Lysine-specific demethylase-1 is involved in the development of PCa and affects the expression and function of AR (127). The high expression of HNRNPA2B1 can promote the proliferation and metastasis of PCa. In a new oncogenic axis HNRNPA2B1/miR-93-5p/FERM domain-containing protein 6, HNRNPA2B1 promotes the maturation of miR-93-5p in an m⁶A-dependent manner. Thus, the expression of tumor suppressor FERM domain-containing protein 6 is reduced (119).

As an epithelial-mesenchymal transition (EMT) regulator in PCa, FTO can inhibit the m⁶A modification level of EMT tumor cells. When the FTO gene is knocked out, EMT occurs in tumor cells, and promotes cell migration and proliferation (128). In addition, it has been shown that NAP1L2 and lncNAP1L6 are involved in the migration, invasion and EMT processes of PCa cells (110).

RNA binding motif 3 over methylated m⁶A on catenin β1 (CTNNB1) mRNA in a manner dependent on METTL3. Alterations in β-catenin signaling can affect stem-like properties and the self-renewal ability of tumor cells. The stability of CTNNB1 mRNA was reduced by methylation of m⁶A. This results in the inactivation of the Wnt signaling pathway, and eventually, the stemness remodeling of PCa cells by osteoblasts was inhibited (129).

The transfer of PCa is associated with m⁶A-modified mRNA. Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) is a technique that combines RNA-protein immunoprecipitation and high-throughput sequencing. MeRIP-Seq can map m⁶A methylated mRNA (130). The score of m⁶A modified mRNA was calculated by the results of MeRIP-Seq. A higher m⁶A-modified mRNA score is associated with a shorter biochemical relapse time in patients with PCa, and m⁶A hypomethylation may contribute to PCa initiation. By contrast, the transfer group exhibits more m⁶A modification peaks than the primary group. MeRIP-Seq helps study the prognosis and diagnosis of PCa (131). MeRIP-seq can also predict the results of PCa by detecting the content of m⁶A methylated lncRNA in PCa tissues and calculating the lncRNA score modified by m⁶A (132).

Compared with normal tissues, malignant tissues of patients with PCa have a lower FTO content and higher m⁶A levels. Higher levels of FTO expression have been detected in patients with PCa with a poor prognosis. This indicates that the expression level of FTO is associated with the prognosis of PCa, suggesting that FTO is one of the diagnostic markers of PCa (133). THBS1 is a tumor suppressor that can inhibit the proliferation of PCa. In the nucleus, METTL14 inhibits THBS1 expression in an m⁶A-dependent manner, leading to PCa proliferation. Therefore, METTL14 may be a prognostic marker and an effective therapeutic target for PCa (104). METTL3 is highly expressed in tumor cells and is predictive of a poor prognosis; thus, it is a promising diagnostic and prognostic marker (134).

The methylation of m⁶A is associated with immune response, tumor growth and metastasis (135). M⁶A regulators cluster 3 modulates METTL14 and ZC3H13 expression levels and increases Th1 cells, Th17 cells, mesenchymal fraction and transforming growth factor-β. Of these, Th1 cells can initiate an antitumor immune response. The interstitial fraction is inversely related to the degree of malignancy of the tumor. TGF-β can inhibit the Th1 response and reduce the effect of ICIs. In addition, Th17 cells are a good prognostic indicator of PCa, which is related to the efficacy of PD-1 blockade in PCa treatment (105). Additionally, it has been shown that the m⁶A methylation regulators HNRNPA2B1 and METTL3 affect the immune microenvironment of PCa (136).

The latest research suggests that the radiosensitivity of tumors can be modulated by methylation modifications of m⁶A, which greatly increase the role of radiotherapy in cancer. The pathogenesis and progression of bone metastatic PCa can be inhibited by deletion of the MLXIPe/KHSRP/PSMD9 regulatory complex in vitro and in vivo, thereby improving the efficacy of radiotherapy. This mechanism is achieved by the RNA-binding protein KHSRP, which simultaneously recognizes m⁶A on the enhancer RNA and m⁶Am on the 5′-UTR, while resisting degradation by the exonuclease XRN2 (137).

METTL3, FTO, YTHDC1-2, YTHDF1-3 and IGF2BP1-3 proteins generally promote tumorigenesis. METTL3, METTL14, FTO and ALKBH5 can promote or inhibit the progression of cancer cells. Similarly, METTL3, FTO and ALKBH5 can alter the susceptibility or resistance of cancer cells to anticancer treatments (138). By identifying appropriate treatments that affect the functions leading to the development of PCa, it may be possible to treat PCa. Treatment with enzalutamide combined with METTL3 knockdown has been shown to result in AR-independent upregulation of gastrointestinal-specific gene features driven by nuclear receptor NR5A2, which result in enzalutamide resistance. This suggests that NR5A2 and other downstream pathway genes may be one of the targets for the treatment of CRPC (83). The functional inhibition of METTL3 may reduce tumor chemotherapeutic resistance induced by METTL3 and restore tumor sensitivity to chemotherapy drugs (134). PCa photothermal immunotherapy is also a treatment direction for PCa. Meclofenamic acid, a highly selective FTO inhibitor, can be combined with a gold nanorod-based nanoplatform to promote photothermal immunotherapy for PCa (139). Curcumin can inhibit the expression of m⁶A-dependent TNF receptor-associated factor 4 induced by ALKBH5 and YTHDF1 (140). In addition, the potentially beneficial effect of curcumin in reducing PSA in patients with intermittent androgen deprivation PCa has also been demonstrated in a clinical trial (141).

Solute carrier family 12 member 5 is a neuron-specific potassium chloride cotransporter 2. Solute carrier family 12 member 5 promotes the tumorigenesis and development of PCa through YTHDC1 and the transcription factor, homeobox B13 (HOXB13). Solute carrier family 12 member 5 inhibitors may be used in the treatment of PCa (142). METTL3 knockdown combined with enzalutamide treatment has been shown to result in the development of resistance to enzalutamide in PCa cells. This suggests the mechanism by which PCa cells develop resistance to enzalutamide and may be an effective therapeutic target (83).

The change in drug delivery has largely enabled precision therapy. The treatment based on nanotechnology can improve the systemic toxicity and low efficacy of paclitaxel, adriamycin, docetaxel and other classical chemotherapy drugs, providing a new exploration direction for the precise targeted therapy of PCa (143). Gold nanoparticles coated with bovine serum albumin can be potentially cytotoxic to PCa (144). Multifunctional self-assembly magnetic nanocarriers can effectively improve the delivery efficiency of prostate tumors in the process of photothermal therapy, which enhances the efficacy of photothermal therapy on PCa and plays an antitumor role (145). The microwave-induced expression of heat shock protein (HSP)70 in prostate tissue and the transfer of HSP70 to the cell membrane have been studied. The HSP70 antibody is then coated with nanoparticles and doxorubicin is precisely ablated and released under near-infrared irradiation, enabling precise drug therapy (146).