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

Overactivated ribosome biogenesis is a common feature of cancer. However, the underlying molecular mechanism remains elusive. Herein, we report enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, could interact with fibrillarin (FBL) directly in the nucleolus. While loss of EZH2 does not impact FBL-mediated histone H2AQ104 methylation (H2AQ104me) and 18S rRNA processing, EZH2 is proved to be involved in rRNA 2′-O methylation in a manner dependent of its interaction with FBL. Mechanistically, EZH2 strengthens the fibrillarin (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 alters translational efficiency and reduces internal ribosome entry site (IRES) activity of key oncogenes in prostate cancer. In summary, our findings reveal a novel non-methyltransferase role of EZH2 that mediates FBL functions, which may provide more options for the development of EZH2-targeting curative strategies in cancer. Examination of 2'-O-Methylation of the rRNA in the siCTRL(3replicates) and siEZH2(2 and 2 replicates) C4-2 cells using ribo-Meth sequencing methed.