Cell Reports (Apr 2018)
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
Affiliations
- Peijing Zhang
- 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; Corresponding author
- Zhenna Xiao
- 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
- Shouyu Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Mutian Zhang
- Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX 77030, USA
- Yongkun Wei
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Qinglei Hang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Jongchan Kim
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Fan Yao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Cristian Rodriguez-Aguayo
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Baochau N. Ton
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Minjung Lee
- 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
- Yumeng Wang
- 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
- Zhicheng Zhou
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Liyong Zeng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Xiaoyu Hu
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Sarah E. Lawhon
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Ashley N. Siverly
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Xiaohua Su
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Jia Li
- Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX 77030, USA
- Xiaoping Xie
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Xuhong Cheng
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Liang-Chiu Liu
- Division of Breast Surgery, Department of Surgery, China Medical University Hospital, Taichung 404, Taiwan
- Hui-Wen Chang
- Department of Pathology, China Medical University Hospital, Taichung 404, Taiwan
- Shu-Fen Chiang
- Cancer Center, China Medical University Hospital, Taichung 404, Taiwan
- Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Anil K. Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Junjie Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- M. James You
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Shao-Cong Sun
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Han Liang
- 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
- Yun Huang
- 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
- Xianbin Yang
- AM Biotechnologies, Houston, TX 77034, USA
- Deqiang Sun
- Center for Epigenetics & Disease Prevention, Texas A&M University Institute of Biosciences & Technology, Houston, TX 77030, USA
- Yutong Sun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Mien-Chie Hung
- 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
- Li Ma
- 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; Corresponding author
- Journal volume & issue
-
Vol. 23,
no. 3
pp. 823 – 837
Abstract
Summary: 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. Keywords: ZRANB1, EZH2, deubiquitinase, breast cancer
