Crosstalk between EZH2 and m6A RNA methylation promotes prostate cancer progression through modulating an m6A autoregulation pathway

N6-methyladenosine (m6A), the most predominant RNA modification in humans, participates in various fundamental and pathological bioprocesses. Dynamic manipulation of m6A deposition in the transcriptome is critical for cancer progression, while how this regulation is achieved remains understudied. Here, we report that in prostate cancer (PCa), Polycomb group (PcG) protein Enhancer of Zeste Homolog 2 (EZH2) exerts an additional function in m6A regulation via its enzymatic activity. Mechanistically, EZH2 methylates and stabilizes FOXA1 proteins from degradation, which in turn facilitates the transcription of m6A reader YTHDF1. Through activating a m6A autoregulation pathway, YTHDF1 enhances the translation of METTL14 and WTAP, two critical components of the m6A methyltransferase complex (MTC), and thereby upregulates the global m6A level in PCa cells. We further demonstrate that inhibiting the catalytic activity of EZH2 suppresses the translation process globally through targeting the YTHDF1-m6A axis. By disrupting both the expression and interaction of key m6A MTC subunits, combinational treatment of EZH2 degrader MS8815 and m6A inhibitor STM2457 mitigates PCa tumor growth synergistically. Together, our study decodes a previously hidden interrelationship between EZH2 and RNA modification, which may be leveraged to advance the EZH2-targeting curative strategies in cancer. Overall design: Nanopore Direct RNA sequencing of C4-2 cells after silencing EZH2 and METTL3, with two replicates each. RNA-sequencing of C4-2 cells after silencing YTHDF1 and treatment with EZH2 enzymatic inhibitor EPZ6438. In parallel, we performed ribosome profiling of both conditions using RiboLace library construction.