| Literature DB >> 29669287 |
Peijing Zhang1, Zhenna Xiao2, Shouyu Wang3, Mutian Zhang4, Yongkun Wei5, Qinglei Hang3, Jongchan Kim3, Fan Yao3, Cristian Rodriguez-Aguayo6, Baochau N Ton3, Minjung Lee7, Yumeng Wang8, Zhicheng Zhou3, Liyong Zeng3, Xiaoyu Hu3, Sarah E Lawhon3, Ashley N Siverly3, Xiaohua Su3, Jia Li4, Xiaoping Xie9, Xuhong Cheng9, Liang-Chiu Liu10, Hui-Wen Chang11, Shu-Fen Chiang12, Gabriel Lopez-Berestein6, Anil K Sood13, Junjie Chen3, M James You14, Shao-Cong Sun9, Han Liang15, Yun Huang7, Xianbin Yang16, Deqiang Sun4, Yutong Sun5, Mien-Chie Hung17, Li Ma18.
Abstract
Although EZH2 enzymatic inhibitors have shown antitumor effects in EZH2-mutated lymphoma and ARID1A-mutated ovarian cancer, many cancers do not respond because EZH2 can promote cancer independently of its histone methyltransferase activity. Here we identify ZRANB1 as the EZH2 deubiquitinase. ZRANB1 binds, deubiquitinates, and stabilizes EZH2. Depletion of ZRANB1 in breast cancer cells results in EZH2 destabilization and growth inhibition. Systemic delivery of ZRANB1 small interfering RNA (siRNA) leads to marked antitumor and antimetastatic effects in preclinical models of triple-negative breast cancer (TNBC). Intriguingly, a small-molecule inhibitor of ZRANB1 destabilizes EZH2 and inhibits the viability of TNBC cells. In patients with breast cancer, ZRANB1 levels correlate with EZH2 levels and poor survival. These findings suggest the therapeutic potential for targeting the EZH2 deubiquitinase ZRANB1.Entities:
Keywords: EZH2; ZRANB1; breast cancer; deubiquitinase
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Year: 2018 PMID： 29669287 PMCID： PMC5933875 DOI： 10.1016/j.celrep.2018.03.078
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423