TY - JOUR
T1 - Prostate cancer-Associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4
AU - Dai, Xiangpeng
AU - Gan, Wenjian
AU - Li, Xiaoning
AU - Wang, Shangqian
AU - Zhang, Wei
AU - Huang, Ling
AU - Liu, Shengwu
AU - Zhong, Qing
AU - Guo, Jianping
AU - Zhang, Jinfang
AU - Chen, Ting
AU - Shimizu, Kouhei
AU - Beca, Francisco
AU - Blattner, Mirjam
AU - Vasudevan, Divya
AU - Buckley, Dennis L.
AU - Qi, Jun
AU - Buser, Lorenz
AU - Liu, Pengda
AU - Inuzuka, Hiroyuki
AU - Beck, Andrew H.
AU - Wang, Liewei
AU - Wild, Peter J.
AU - Garraway, Levi A.
AU - Rubin, Mark A.
AU - Barbieri, Christopher E.
AU - Wong, Kwok Kin
AU - Muthuswamy, Senthil K.
AU - Huang, Jiaoti
AU - Chen, Yu
AU - Bradner, James E.
AU - Wei, Wenyi
N1 - Funding Information:
We thank N. Mitsiades (Baylor College of Medicine), P. Zhou (Weill Cornell Medical College), W. Kaelin (Dana-Farber Cancer Institute), C. French (Brigham and Women’s Hospital), R.-H. Chen (Institute of Biological Chemistry, Academia Sinica), S. Uchida (Tokyo Medical and Dental University), J. Yuan (Harvard Medical School) and S.-Y. Shao (Beth Israel Deaconess Medical Center) for their contributed materials. We thank F. Wu, B. Wang, N.T. Nihira and B. North for critical reading of the manuscript and members of the Wei and Bradner laboratories for useful discussions. X.D. and J.G. are supported by a National Research Service Award T-32 training grant. W.G. is supported by 1K99CA207867 from the National Cancer Institute. D.L.B. is a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2196-14). P.J.W. is funded in part by a H2020 grant from the European Commission (PrECISE) and a research grant from the University of Zurich, Switzerland. W.W. is an American Cancer Society research scholar. This work was supported in part by National Institutes of Health grants (W.W., GM094777 and CA177910).
PY - 2017/9/1
Y1 - 2017/9/1
N2 - The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3 SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-Associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.
AB - The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3 SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-Associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.
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U2 - 10.1038/nm.4378
DO - 10.1038/nm.4378
M3 - Article
C2 - 28805820
AN - SCOPUS:85029059604
SN - 1078-8956
VL - 23
SP - 1063
EP - 1071
JO - Nature Medicine
JF - Nature Medicine
IS - 9
ER -