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Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation 期刊论文

编号：

586f21d1-98ef-4f84-a5c7-252f038ff301
作者：

Zhang, Pingzhao(章平肇)^[1,2,3]Wang, Dejie^[4,5,6];Zhao, Yu^[4];Ren, Shancheng^[7];Gao, Kun^[1];Ye, Zhenqing^[8];Wang, Shangqian^[9];Pan, ChunWu^[4];Zhu, Yasheng^[7];Yan, Yuqian^[4];Yang, Yinhui^[4];Wu, Di^[4];He, Yundong^[4];Zhang, Jun^[10];Lu, Daru^[1];Liu, Xiuping(刘秀萍)^[11]Yu, Long^[1];Zhao, Shimin^[1];Li, Yao^[1];Lin, Dong^[12];Wang, Yuzhuo^[12];Wang, Liguo^[8];Chen, Yu^[9];Sun, Yinghao^[7];Wang, Chenji^[1];Huang, Haojie^[4,6,13];
语种：

English
期刊：

NATURE MEDICINE ISSN：1078-8956 2017 年 23 卷 9 期 (1055 - +) ; SEP
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摘要：

Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors. Transcriptome and BRD4 cistrome analyses reveal enhanced expression of the GTPase RAC1 and cholesterol-biosynthesis-associated genes together with activation of AKT-mTORC1 signaling as a consequence of BRD4 stabilization. Our data show that resistance to BET inhibitors in SPOP-mutant prostate cancer can be overcome by combination with AKT inhibitors and further support the evaluation of SPOP mutations as biomarkers to guide BET-inhibitor-oriented therapy in patients with prostate cancer.
推荐引用方式
GB/T 7714：

Zhang Pingzhao,Wang Dejie,Zhao Yu, et al. Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation [J].NATURE MEDICINE,2017,23(9):1055-+.
APA：

Zhang Pingzhao,Wang Dejie,Zhao Yu,Ren Shancheng,&Huang Haojie.(2017).Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation .NATURE MEDICINE,23(9):1055-+.
MLA：

Zhang Pingzhao, et al. "Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation" .NATURE MEDICINE 23,9(2017):1055-+.

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