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; Rodríguez-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; Chiang, Shu‐Fen; López-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

doi:10.1016/j.celrep.2018.03.078

Cited by 42 publications

(35 citation statements)

References 53 publications

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“…Several E3 ubiquitin ligases have been reported for ubiquitinmediated EZH2 degradation (Wang et al, 2018). In the re-verse process, DUBs, including USP21 and ZRANB1, deubiquitinate and increase the protein stability of EZH2 (Chen et al, 2017;Zhang et al, 2018). We previously reported the deubiquitinating activity of USP44 and subsequent EZH2 protein stabilization in prostate cancer cells and suggested that targeting USP44 might be an efficient anticancer strategy for EZH2-dependent cancers irrespective of the enzymatic activity of EZH2 (Park et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…EZH2 ubiquitination by several E3 ubiquitin ligases and subsequent proteasome-mediated degradation have been described in a few tissues and distinct physiological conditions (Wang et al, 2018). Further, DUBs, including USP21 and ZRANB1, targeting EZH2 function and protein stability have been studied (Chen et al, 2017;Zhang et al, 2018). Recently, we reported the deubiquitinating activity of USP44 and the subsequent stabilization of EZH2 protein in prostate cancer cells (Park et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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USP7 deubiquitinates and stabilizes EZH2 in prostate cancer cells

2020

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Regulation of target proteins by the ubiquitin-proteasome system (UPS) is common in a wide range of cellular events, including transcriptional regulation, cell cycle progression, differentiation, and tumorigenesis. Ubiquitinspecific protease 7 (USP7) has been implicated in tumor development and metastasis in various malignancies through the regulation of target protein stability. In this study, we found that the enhancer of zeste homolog 2 (EZH2), which catalyzes the methylation at lysine 27 of histone H3, is a target of USP7 and is stabilized by USP7-mediated deubiquitination. In prostate cancer cells, the transcriptional repression function of EZH2 was inhibited by USP7knockdown. Furthermore, ectopic introduction of EZH2 restored the cell migration, invasion, and sphere-forming potential of prostate cancer cells, which had been decreased by USP7-knockdown. Moreover, combined treatment with the USP7-specific inhibitor P5091 and EZH2 inhibitors, such as GSK126, EPZ6438, and DZNep, induced synergistic inhibitory effects on cell migration, invasion, and sphere-forming potential in prostate cancer cells. Collectively, our findings revealed that the promotion of the malignancy-associated characteristics of prostate cancer cells by USP7 was in part due to EZH2 stabilization. Thus, we suggest that simultaneous treatment with a USP7 inhibitor and an EZH2 inhibitor could be a rational strategy for treating EZH2-dependent cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

USP7 deubiquitinates and stabilizes EZH2 in prostate cancer cells

2020

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“…In addition to DCAF1, described above, these candidate genes include ZRANB1 and CTBP2 located on 10q26.13. ZRANB1 is a deubiquitinase targeting, e.g., EZH2, a component of the PRC2 and direct regulator of BRCA1 activation 47,48 , whereas CTBP2 is a transcriptional corepressor priming target gene promoters, including BRCA1, for PRC2-dependent silencing 49,50 .…”

Section: Discussionmentioning

confidence: 99%

Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

et al. 2020

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Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03–6.30, P = 3.1 × 10−9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

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“…During preparation of this manuscript, two other deubiquitinases, USP21 and ZRANB1, have been reported to stabilize EZH2 in different biology contexts. Chen and colleagues identify that USP21 can deubiquitinate and stabilize EZH2 to promote cell proliferation and metastasis in bladder carcinoma (31); Zhang and colleagues find that ZRANB1 is an EZH2 deubiquitinase and regulates EZH2 function in breast cancer through both catalytic activity-dependent and -independent manner (32). Herein, our study identifies USP1 as a novel deubiquitinase, which stabilizes EZH2 during glioma tumorigenesis, and demonstrates that the USP1-EZH2 axis plays a critical role in the malignant transformation of glioma cells.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Activation of β-Catenin Signaling Drives Glioma Tumorigenesis via USP1-Mediated Stabilization of EZH2

Lin

Chang

et al. 2019

Cancer Research

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Aberrant activation of b-catenin signaling is a critical driver for tumorigenesis, but the mechanism underlying this activation is not completely understood. In this study, we demonstrate a critical role of b-catenin signaling in stabilization of enhancer of zeste homolog 2 (EZH2) and control of EZH2mediated gene repression in oncogenesis. b-Catenin/TCF4 activated the transcription of the deubiquitinase USP1, which then interacted with and deubiquitinated EZH2 directly. USP1-mediated stabilization of EZH2 promoted its recruitment to the promoters of CDKN1B, RUNX3, and HOXA5, resulting in enhanced enrichment of histone H3K27me3 and repression of target gene expression. In human glioma specimens , expression levels of nuclear b-catenin, USP1, and EZH2 correlated with one another. Depletion of b-catenin/USP1/ EZH2 repressed glioma cell proliferation in vitro and tumor formation in vivo. Our findings indicate that a b-catenin-USP1-EZH2 axis orchestrates the interplay between dysregulated b-catenin signaling and EZH2-mediated gene epigenetic silencing during glioma tumorigenesis. Significance: These findings identify the b-catenin-USP1-EZH2 signaling axis as a critical mechanism for glioma tumorigenesis that may serve as a new therapeutic target in glioblastoma.

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

Cited by 42 publications

References 53 publications

USP7 deubiquitinates and stabilizes EZH2 in prostate cancer cells

USP7 deubiquitinates and stabilizes EZH2 in prostate cancer cells

Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

Aberrant Activation of β-Catenin Signaling Drives Glioma Tumorigenesis via USP1-Mediated Stabilization of EZH2

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