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 Lin

Yuzhuo Wang, Liguo Wang, Yu Chen, Yinghao Sun^*, Chenji Wang, Haojie Huang

^*Corresponding author for this work

Fudan University
Mayo Clinic Rochester, MN
Nanchang University
Mayo Clinic College of Medicine
Second Military Medical University
Memorial Sloan-Kettering Cancer Center
Provincial Health Services Authority

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

260 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
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 - 1 Sep 2017
Externally published	Yes

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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

@article{fc06b3e2561f44eca4da71822b522360,

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",

year = "2017",

month = sep,

day = "1",

doi = "10.1038/nm.4379",

language = "英语",

volume = "23",

pages = "1055--1062",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

number = "9",

}

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

TY - JOUR

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

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.

UR - https://www.scopus.com/pages/publications/85029067658

U2 - 10.1038/nm.4379

DO - 10.1038/nm.4379

M3 - 文章

C2 - 28805822

AN - SCOPUS:85029067658

SN - 1078-8956

VL - 23

SP - 1055

EP - 1062

JO - Nature Medicine

JF - Nature Medicine

IS - 9

ER -

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

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