DUB3 Promotes BET Inhibitor Resistance and Cancer Progression by Deubiquitinating BRD4

被引：126
作者：
Jin, Xin [1 ,2 ]
Yan, Yuqian [2 ]
Wang, Dejie [2 ]
Ding, Donglin [2 ]
Ma, Tao [2 ]
Ye, Zhenqing [3 ]
Jimenez, Rafael [4 ]
Wang, Liguo [3 ]
Wu, Heshui [1 ]
Huang, Haojie [2 ,5 ,6 ]
机构：
[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dep Pancreat Surg, Wuhan 430022, Hubei, Peoples R China
[2] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA
[3] Mayo Clin, Coll Med, Div Biomed Stat & Informat, Rochester, MN 55905 USA
[4] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN 55905 USA
[5] Mayo Clin, Coll Med, Dept Urol, Rochester, MN 55905 USA
[6] Mayo Clin, Coll Med, Canc Ctr, Rochester, MN 55905 USA
来源：
MOLECULAR CELL | 2018年 / 71卷 / 04期
基金：
中国国家自然科学基金;
关键词：
BROMODOMAIN PROTEIN BRD4; BREAST-CANCER; PROSTATE-CANCER; STEM-CELLS; TRANSCRIPTION; SUPPRESSES; ACTIVATION; CHROMATIN; DEGRADATION; PALBOCICLIB;
D O I：
10.1016/j.molcel.2018.06.036
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
The bromodomain and extra-terminal domain (BET) protein BRD4 is emerging as a promising anticancer therapeutic target. However, resistance to BET inhibitors often occurs, and it has been linked to aberrant degradation of BRD4 protein in cancer. Here, we demonstrate that the deubiquitinase DUB3 binds to BRD4 and promotes its deubiquitination and stabilization. Expression of DUB3 is transcriptionally repressed by the NCOR2-HDAC10 complex. The NCOR2 gene is frequently deleted in castration-resistant prostate cancer patient specimens, and loss of NCOR2 induces elevation of DUB3 and BRD4 proteins in cancer cells. DUB3-proficient prostate cancer cells are resistant to the BET inhibitor JQ1 in vitro and in mice, but this effect is diminished by DUB3 inhibitory agents such as CDK4/6 inhibitor in a RB-independent manner. Our findings identify a previously unrecognized mechanism causing BRD4 upregulation and drug resistance, suggesting that DUB3 is a viable therapeutic target to overcome BET inhibitor resistance in cancer.
引用
收藏
页码：592 / +
页数：18
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