A PRC2-independent function for EZH2 in regulating rRNA 2′-O methylation and IRES-dependent translation

Abstract

Uncontrolled translation is a common feature of cancer. Uncovering its governing factors and underlying mechanism are important for cancer therapy. Herein, we report that enhancer of zeste homolog 2 (EZH2), previously known as a transcription repressor and lysine methyltransferase, could directly interact with fibrillarin (FBL) to exert its role in translational regulation. We demonstrate that EZH2 enhances rRNA 2′-O-Me via its direct interaction with FBL, while loss of EZH2 does not impact FBL-mediated histone H2AQ104 methylation (H2AQ104me). Mechanistically, EZH2 strengthens the FBL-NOP56 interaction by binding to both proteins and thus facilitates the assembly of box C/D small nucleolar ribonucleoprotein (box C/D snoRNP). Strikingly, EZH2 deficiency impairs the translation process globally and reduces internal ribosome entry site (IRES)-dependent translation initiation in cancer cells. Our findings reveal a previously unrecognized role of EZH2 in translational regulation, which may provide a new option for the development of EZH2-targeting curative strategies in cancer.