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

Pingzhao Zhang; Dejie Wang; Yu Zhao; Shancheng Ren; Kun Gao; Zhenqing Ye; Shangqian Wang; Chun Wu Pan; Yasheng Zhu; Yuqian Yan; Yinhui Yang; Di Wu; Yundong He; Jun Zhang; Daru Lu; Xiuping Liu; Long Yu; Shimin Zhao; Yao Li; Dong Lin; Yuzhuo Wang; Liguo Wang; Yu Chen; Yinghao Sun; Chenji Wang; Haojie Huang

doi:10.1038/nm.4379

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

Pingzhao Zhang, Dejie Wang, Yu Zhao, Shancheng Ren, Kun Gao, Zhenqing Ye, Shangqian Wang, Chun Wu Pan, Yasheng Zhu, Yuqian Yan, Yinhui Yang, Di Wu, Yundong He, Jun Zhang, Daru Lu, Xiuping Liu, Long Yu, Shimin Zhao, Yao Li, Dong LinYuzhuo Wang, Liguo Wang, Yu Chen, Yinghao Sun, Chenji Wang, Haojie Huang

Research output: Contribution to journal › Article › peer-review

117 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1055-1062
Number of pages	8
Journal	Nature Medicine
Volume	23
Issue number	9
DOIs	https://doi.org/10.1038/nm.4379
State	Published - Sep 1 2017

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm.4379

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Zhang, P., Wang, D., Zhao, Y., Ren, S., Gao, K., Ye, Z., Wang, S., Pan, C. W., Zhu, Y., Yan, Y., Yang, Y., Wu, D., He, Y., Zhang, J., Lu, D., Liu, X., Yu, L., Zhao, S., Li, Y., ... Huang, H. (2017). Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation. Nature Medicine, 23(9), 1055-1062. https://doi.org/10.1038/nm.4379

Zhang, P, Wang, D, Zhao, Y, Ren, S, Gao, K, Ye, Z, Wang, S, Pan, CW, Zhu, Y, Yan, Y, Yang, Y, Wu, D, He, Y, Zhang, J, Lu, D, Liu, X, Yu, L, Zhao, S, Li, Y, Lin, D, Wang, Y, Wang, L, Chen, Y, Sun, Y, Wang, C & Huang, H 2017, 'Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation', Nature Medicine, vol. 23, no. 9, pp. 1055-1062. https://doi.org/10.1038/nm.4379

@article{7ebf13ca066e42d8b1d5ebd55ba986ae,

title = "Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation",

abstract = "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.",

author = "Pingzhao Zhang and Dejie Wang and Yu Zhao and Shancheng Ren and Kun Gao and Zhenqing Ye and Shangqian Wang and Pan, {Chun Wu} and Yasheng Zhu and Yuqian Yan and Yinhui Yang and Di Wu and Yundong He and Jun Zhang and Daru Lu and Xiuping Liu and Long Yu and Shimin Zhao and Yao Li and Dong Lin and Yuzhuo Wang and Liguo Wang and Yu Chen and Yinghao Sun and Chenji Wang and Haojie Huang",

note = "Funding Information: This work was supported in part by grants from the National Institutes of Health (CA134514, CA130908 and CA193239 to H.H.), the US Department of Defense (W81XWH-09-1-622 to H.H.), the National Natural Science Foundation of China (81672558 and 81201533 to C.W.; 81572768 to P.Z.; 31560320 to D. Wang; 31400753 to K.G.), and the National Key Research and Development Plan of China–Precision Medicine Project (2016YFC0902202 to Y.S., C.W. and S.R.).",

year = "2017",

month = sep,

day = "1",

doi = "10.1038/nm.4379",

language = "English (US)",

volume = "23",

pages = "1055--1062",

journal = "Nature Medicine",

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T1 - Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation

AU - Zhang, Pingzhao

AU - Wang, Dejie

AU - Zhao, Yu

AU - Ren, Shancheng

AU - Gao, Kun

AU - Ye, Zhenqing

AU - Wang, Shangqian

AU - Pan, Chun Wu

AU - Zhu, Yasheng

AU - Yan, Yuqian

AU - Yang, Yinhui

AU - Wu, Di

AU - He, Yundong

AU - Zhang, Jun

AU - Lu, Daru

AU - Liu, Xiuping

AU - Yu, Long

AU - Zhao, Shimin

AU - Li, Yao

AU - Lin, Dong

AU - Wang, Yuzhuo

AU - Wang, Liguo

AU - Chen, Yu

AU - Sun, Yinghao

AU - Wang, Chenji

AU - Huang, Haojie

N1 - Funding Information: This work was supported in part by grants from the National Institutes of Health (CA134514, CA130908 and CA193239 to H.H.), the US Department of Defense (W81XWH-09-1-622 to H.H.), the National Natural Science Foundation of China (81672558 and 81201533 to C.W.; 81572768 to P.Z.; 31560320 to D. Wang; 31400753 to K.G.), and the National Key Research and Development Plan of China–Precision Medicine Project (2016YFC0902202 to Y.S., C.W. and S.R.).

PY - 2017/9/1

Y1 - 2017/9/1

N2 - 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.

AB - 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.

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JO - Nature Medicine

JF - Nature Medicine

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ER -

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

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