METTL3 Promotes Castration-Resistant Prostate Cancer Progression by Enhancing AKR1C3 Expression.

Castration-resistant prostate cancer (CRPC) is a lethal stage of prostate cancer (PC). This research sought to examine the functions and underlying mechanisms of N6-methyladenosine (m6A) methyltransferases in CRPC. Transcriptomic datasets from the Gene Expression Omnibus and The Cancer Genome Atlas were analyzed to identify dysregulated m6A methyltransferases. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine incorporation, wound healing, Transwell, enzyme-linked immunosorbent assay, reverse transcription quantitative polymerase chain reaction, western blot, m6A RNA immunoprecipitation quantitative PCR, co-immunoprecipitation, and m6A quantification assays were performed to evaluate the phenotypic and molecular effects of methyltransferase-like 3 (METTL3). A xenograft tumor model was constructed by subcutaneous injection of lentivirus-transduced LNCaP cells into BALB/c nude mice. Hematoxylin and eosin staining was utilized to detect histopathological alterations, and immunohistochemistry was applied to measure Ki67 expression. METTL3 and methyltransferase-like 5 were upregulated, whereas methyltransferase-like 4 was downregulated. METTL3 knockdown suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transition in LNCaP and C4-2 cells and suppressed xenograft tumor growth. METTL3 knockdown reduced dihydrotestosterone production and suppressed the protein expression of androgen receptor, kallikrein-related peptidase 3, and FK506 binding protein 5. METTL3 enhanced the m6A methylation and transcript stability of aldo-keto reductase family 1 member C3 (AKR1C3). AKR1C3 overexpression notably reversed the anti-tumor effects induced by METTL3 knockdown. METTL3 acts as an epigenetic driver of CRPC by promoting AKR1C3 expression in an m6A-dependent manner, highlighting the METTL3/AKR1C3 axis as a promising treatment target.