N6-methyladenosine RNA methylation regulators contribute to the progression of prostate cancer

Prostate cancer (PCa) is one of the most common epithelial malignant tumors and the fifth leading cause of cancer death in men. An increasing number of studies have demonstrated that N6-methyladenosine (m(6)A) plays a crucial role in tumorigenesis and tumor development. However, little is known about the role and levels of common m(6)A regulators and m(6)A levels in PCa. In this study, we analyzed the characteristic expression of m(6)A regulators in PCa and castration-resistant prostate cancer (CRPC). UALCAN and cBioPortal were used to estimate the clinical value and genetic alterations of m(6)A regulators, respectively. The correlation between m(6)A regulators and androgen receptor (AR) was assessed using Gene Expression Profiling Interactive Analysis (GEPIA) by Pearson correlation statistics. Total m(6)A levels were detected in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and PCa cell lines. Results showed that the expression of methyltransferase-like 3 (METTL3) and YTH domain family members, namely, YTHDC2, YTHDF1, and YTHDF2 were generally upregulated in PCa, whereas those of fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5), and methyltransferase-like 14 (METTL14) were downregulated. The expression of METTL3, METTL14, Wilms' tumor 1-associating protein (WTAP), YTHDC2, YTHDF1, and YTHDF2 were remarkably higher in CRPC with lymph node metastasis than that in CRPC with bone metastasis, whereas ALKBH5, FTO, and YTHDF3 significantly decreased in CRPC with lymph node metastasis tissues. YTHDF1, YTHDF2, and YTHDC2 were positively correlated with the Gleason grades of PCa, and METTL14, FTO, and ALKBH5 were negatively associated with the Gleason classification. M(6)A regulators were positively correlated with AR. Patients with a genomic alteration of m(6)A were associated with poor disease-free survival (DFS). The total m(6)A levels in TRAMP mice increased dramatically compared with those in tumor-free mice, and m(6)A levels in LNCaP cell lines were higher than DU145 and PC3 cell lines. In summary, METTL3, METTL14, ALKBH5, FTO, YTHDC2, YTHDF1, and YTHDF2 were abnormally expressed in PCa and related to Gleason classification. Changes in m(6)A levels maybe contributed to the development and progression of PCa.