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 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

doi:10.1016/j.celrep.2018.03.078

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

Cell Rep. 2018 Apr 17;23(3):823-837. doi: 10.1016/j.celrep.2018.03.078.

Authors

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

Affiliations

¹ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China. Electronic address: zhangpeijing@hust.edu.cn.
² Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Science, Houston, TX 77030, USA.
³ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX 77030, USA.
⁵ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX 77030, USA; Department of Molecular & Cellular Medicine, College of Medicine, Texas A&M University, College Station, TX 77843, USA.
⁸ Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Division of Breast Surgery, Department of Surgery, China Medical University Hospital, Taichung 404, Taiwan.
¹¹ Department of Pathology, China Medical University Hospital, Taichung 404, Taiwan.
¹² Cancer Center, China Medical University Hospital, Taichung 404, Taiwan.
¹³ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁴ Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁵ Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁶ AM Biotechnologies, Houston, TX 77034, USA.
¹⁷ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
¹⁸ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Science, Houston, TX 77030, USA. Electronic address: lma4@mdanderson.org.

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.

Keywords: EZH2; ZRANB1; breast cancer; deubiquitinase.

MeSH terms

Animals
Cell Line, Tumor
Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors
Enhancer of Zeste Homolog 2 Protein / genetics
Enhancer of Zeste Homolog 2 Protein / metabolism
Female
HEK293 Cells
Humans
Kaplan-Meier Estimate
Mice
Mice, Inbred C57BL
Protein Binding
RNA Interference
RNA, Small Interfering / metabolism
RNA, Small Interfering / therapeutic use
Transplantation, Heterologous
Triple Negative Breast Neoplasms / drug therapy
Triple Negative Breast Neoplasms / mortality
Triple Negative Breast Neoplasms / pathology*
Ubiquitin-Specific Proteases / antagonists & inhibitors
Ubiquitin-Specific Proteases / genetics
Ubiquitin-Specific Proteases / metabolism*
Zinc Fingers

Substances

RNA, Small Interfering
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Ubiquitin-Specific Proteases

Abstract

MeSH terms

Substances

Grants and funding