ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2018 Apr 19

PMID 29669287

Citations 28

Authors

Peijing Zhang

Zhenna Xiao

Shouyu Wang

Mutian Zhang

Yongkun Wei

Qinglei Hang

Jongchan Kim

Fan Yao

Cristian Rodriguez-Aguayo

Baochau N Ton

Minjung Lee

Yumeng Wang

Zhicheng Zhou

Liyong Zeng

Xiaoyu Hu

Sarah E Lawhon

Ashley N Siverly

Xiaohua Su

Jia Li

Xiaoping Xie

Xuhong Cheng

Liang-Chiu Liu

Hui-Wen Chang

Shu-Fen Chiang

Gabriel Lopez-Berestein

Anil K Sood

Junjie Chen

M James You

Shao-Cong Sun

Han Liang

Yun Huang

Xianbin Yang

Deqiang Sun

Yutong Sun

Mien-Chie Hung

Li Ma

Affiliations

Soon will be listed here.

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.

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