METTL3 Promotes Castration‐Resistant Prostate Cancer Progression by Enhancing AKR1C3 Expression

ABSTRACT

Castration‐resistant prostate cancer (CRPC) is a lethal stage of prostate cancer (PC). This research sought to examine the functions and underlying mechanisms of N ⁶ ‐methyladenosine (m ⁶ A) methyltransferases in CRPC. Transcriptomic datasets from the Gene Expression Omnibus and The Cancer Genome Atlas were analyzed to identify dysregulated m ⁶ A 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, m ⁶ A RNA immunoprecipitation quantitative PCR, co‐immunoprecipitation, and m ⁶ A 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 m ⁶ A 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 m ⁶ A‐dependent manner, highlighting the METTL3/AKR1C3 axis as a promising treatment target.