Genetic wiring of the m6A epitranscriptome drives prostate cancer progression

Abstract N6-methyladenosine (m6A) is a pervasive RNA modification that modulates transcript stability and translation, yet how m6A deposition is coordinated with transcriptional programs and genetic context during cancer progression remains incompletely understood. Here, we integrate population-resolved m6A profiling with genomics, proteomics and functional modeling to delineate a conserved but selectively reprogrammed epitranscriptomic landscape associated with prostate cancer progression across ancestries. We identify recurrent alteration of ZC3H13, a core m6A regulator, as a central determinant of tumor-specific m6A attenuation and gene-level methylation reprogramming. An m6A regulator-derived risk score robustly stratifies clinical outcomes across multiple independent cohorts. Genetic and in vivo modeling establish ZC3H13 as a causal driver of tumor growth, invasion, and metastasis. Mechanistically, ZC3H13 physically associates with RNA polymerase II and functions as a transcription-coupling scaffold that directs site-specific, co-transcriptional m6A deposition on oncogenic transcripts. This program operates in a genetic context-dependent manner, reinforcing PI3K-AKT signaling in PTEN-intact tumors while sustaining TGF-β/SMAD-driven epithelial-mesenchymal transition following PTEN loss. Collectively, our findings define a transcription-coupled mechanism through which cancer genomes encode epitranscriptomic states and nominate ZC3H13-mediated m6A regulation as a potential genetically-informed therapeutic vulnerability.