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

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 XieXuhong 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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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. Many cancer cells are sensitive to depletion of EZH2 but resistant to EZH2 inhibitors, due to EZH2's enzyme-independent cancer-promoting function. Zhang et al. identify ZRANB1 as an EZH2 deubiquitinase and a potential anticancer target.

Original languageEnglish (US)
Pages (from-to)823-837
Number of pages15
JournalCell Reports
Volume23
Issue number3
DOIs
StatePublished - Apr 17 2018

Fingerprint

Cells
Triple Negative Breast Neoplasms
Breast Neoplasms
Small Interfering RNA
Neoplasms
Molecules
Enzymes
Therapeutics
Ovarian Neoplasms
Lymphoma
Survival
Deubiquitinating Enzymes
Growth
histone methyltransferase

Keywords

  • EZH2
  • ZRANB1
  • breast cancer
  • deubiquitinase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer. / Zhang, Peijing; Xiao, Zhenna; Wang, Shouyu; Zhang, Mutian; Wei, Yongkun; Hang, Qinglei; Kim, Jongchan; Yao, Fan; Rodriguez-Aguayo, Cristian; Ton, Baochau N.; Lee, Minjung; Wang, Yumeng; Zhou, Zhicheng; Zeng, Liyong; Hu, Xiaoyu; Lawhon, Sarah E.; Siverly, Ashley N.; Su, Xiaohua; Li, Jia; Xie, Xiaoping; Cheng, Xuhong; Liu, Liang Chiu; Chang, Hui Wen; Chiang, Shu Fen; Lopez-Berestein, Gabriel; Sood, Anil K.; Chen, Junjie; You, M. James; Sun, Shao Cong; Liang, Han; Huang, Yun; Yang, Xianbin; Sun, Deqiang; Sun, Yutong; Hung, Mien Chie; Ma, Li.

In: Cell Reports, Vol. 23, No. 3, 17.04.2018, p. 823-837.

Research output: Contribution to journalArticle

Zhang, P, Xiao, Z, Wang, S, Zhang, M, Wei, Y, Hang, Q, Kim, J, Yao, F, Rodriguez-Aguayo, C, Ton, BN, Lee, M, Wang, Y, Zhou, Z, Zeng, L, Hu, X, Lawhon, SE, Siverly, AN, Su, X, Li, J, Xie, X, Cheng, X, Liu, LC, Chang, HW, Chiang, SF, Lopez-Berestein, G, Sood, AK, Chen, J, You, MJ, Sun, SC, Liang, H, Huang, Y, Yang, X, Sun, D, Sun, Y, Hung, MC & Ma, L 2018, 'ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer', Cell Reports, vol. 23, no. 3, pp. 823-837. https://doi.org/10.1016/j.celrep.2018.03.078
Zhang, Peijing ; Xiao, Zhenna ; Wang, Shouyu ; Zhang, Mutian ; Wei, Yongkun ; Hang, Qinglei ; Kim, Jongchan ; Yao, Fan ; Rodriguez-Aguayo, Cristian ; Ton, Baochau N. ; Lee, Minjung ; Wang, Yumeng ; Zhou, Zhicheng ; Zeng, Liyong ; Hu, Xiaoyu ; Lawhon, Sarah E. ; Siverly, Ashley N. ; Su, Xiaohua ; Li, Jia ; Xie, Xiaoping ; Cheng, Xuhong ; Liu, Liang Chiu ; Chang, Hui Wen ; Chiang, Shu Fen ; Lopez-Berestein, Gabriel ; Sood, Anil K. ; Chen, Junjie ; You, M. James ; Sun, Shao Cong ; Liang, Han ; Huang, Yun ; Yang, Xianbin ; Sun, Deqiang ; Sun, Yutong ; Hung, Mien Chie ; Ma, Li. / ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer. In: Cell Reports. 2018 ; Vol. 23, No. 3. pp. 823-837.
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AU - Zhang, Peijing

AU - Xiao, Zhenna

AU - Wang, Shouyu

AU - Zhang, Mutian

AU - Wei, Yongkun

AU - Hang, Qinglei

AU - Kim, Jongchan

AU - Yao, Fan

AU - Rodriguez-Aguayo, Cristian

AU - Ton, Baochau N.

AU - Lee, Minjung

AU - Wang, Yumeng

AU - Zhou, Zhicheng

AU - Zeng, Liyong

AU - Hu, Xiaoyu

AU - Lawhon, Sarah E.

AU - Siverly, Ashley N.

AU - Su, Xiaohua

AU - Li, Jia

AU - Xie, Xiaoping

AU - Cheng, Xuhong

AU - Liu, Liang Chiu

AU - Chang, Hui Wen

AU - Chiang, Shu Fen

AU - Lopez-Berestein, Gabriel

AU - Sood, Anil K.

AU - Chen, Junjie

AU - You, M. James

AU - Sun, Shao Cong

AU - Liang, Han

AU - Huang, Yun

AU - Yang, Xianbin

AU - Sun, Deqiang

AU - Sun, Yutong

AU - Hung, Mien Chie

AU - Ma, Li

PY - 2018/4/17

Y1 - 2018/4/17

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