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

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 journal › Article › peer-review

37 Scopus citations

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 language	English (US)
Pages (from-to)	823-837
Number of pages	15
Journal	Cell Reports
Volume	23
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2018.03.078
State	Published - Apr 17 2018

Keywords

EZH2
ZRANB1
breast cancer
deubiquitinase

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

Bioinformatics Shared Resource
Functional Genomics Core
Research Animal Support Facility
Small Animal Imaging Facility

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10.1016/j.celrep.2018.03.078

Cite this

Zhang, P., Xiao, Z., Wang, S., Zhang, M., Wei, Y., Hang, Q., Kim, J., Yao, F., Rodriguez-Aguayo, C., Ton, B. N., Lee, M., Wang, Y., Zhou, Z., Zeng, L., Hu, X., Lawhon, S. E., Siverly, A. N., Su, X., Li, J., ... Ma, L. (2018). ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer. Cell Reports, 23(3), 823-837. https://doi.org/10.1016/j.celrep.2018.03.078

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

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title = "ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer",

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.",

keywords = "EZH2, ZRANB1, breast cancer, deubiquitinase",

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

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s)",

year = "2018",

month = apr,

day = "17",

doi = "10.1016/j.celrep.2018.03.078",

language = "English (US)",

volume = "23",

pages = "823--837",

journal = "Cell Reports",

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T1 - ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer

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

N2 - 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.

AB - 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.

KW - EZH2

KW - ZRANB1

KW - breast cancer

KW - deubiquitinase

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DO - 10.1016/j.celrep.2018.03.078

M3 - Article

C2 - 29669287

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SN - 2211-1247

VL - 23

SP - 823

EP - 837

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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