Person:

Li, Yanqiang

Cell division cycle associated 8 (CDCA8) is a component of chromosomal passenger complex (CPC) that participates in mitotic regulation. Although cancer-related CDCA8 hyperactivation has been widely observed, its molecular mechanism remains elusive. Here, we report that CDCA8 overexpression maintains tumorigenicity and is associated with poor clinical outcome in patients with prostate cancer (PCa). Notably, enhancer of zeste homologue 2 (EZH2) is identified to be responsible for CDCA8 activation in PCa. Genome-wide assays revealed that EZH2-induced H3K27 trimethylation represses let-7b expression and thus protects the let-7b-targeting CDCA8 transcripts. More importantly, EZH2 facilitates the self-activation of E2F1 by recruiting E2F1 to its own promoter region in a methylation-independent manner. The high level of E2F1 further promotes transcription of CDCA8 along with the other CPC subunits. Taken together, our study suggests that EZH2-mediated cell cycle regulation in PCa relies on both its methyltransferase and non-methyltransferase activities.

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.