Prostate cancer-Associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4

Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L. Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki InuzukaAndrew H. Beck, Liewei M Wang, Peter J. Wild, Levi A. Garraway, Mark A. Rubin, Christopher E. Barbieri, Kwok Kin Wong, Senthil K. Muthuswamy, Jiaoti Huang, Yu Chen, James E. Bradner, Wenyi Wei

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1063-1071
Number of pages9
JournalNature Medicine
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2017

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Prostatic Neoplasms
Stabilization
Mutation
Proteins
Neoplasms
Bearings (structural)
Cullin Proteins
Cells
Organoids
Apoptosis
Degradation
Growth Inhibitors
Molecular Models
Protein Stability
Ubiquitination
Cell growth
Testis
Tumors
Cell Cycle
Protein Isoforms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Prostate cancer-Associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. / Dai, Xiangpeng; Gan, Wenjian; Li, Xiaoning; Wang, Shangqian; Zhang, Wei; Huang, Ling; Liu, Shengwu; Zhong, Qing; Guo, Jianping; Zhang, Jinfang; Chen, Ting; Shimizu, Kouhei; Beca, Francisco; Blattner, Mirjam; Vasudevan, Divya; Buckley, Dennis L.; Qi, Jun; Buser, Lorenz; Liu, Pengda; Inuzuka, Hiroyuki; Beck, Andrew H.; Wang, Liewei M; Wild, Peter J.; Garraway, Levi A.; Rubin, Mark A.; Barbieri, Christopher E.; Wong, Kwok Kin; Muthuswamy, Senthil K.; Huang, Jiaoti; Chen, Yu; Bradner, James E.; Wei, Wenyi.

In: Nature Medicine, Vol. 23, No. 9, 01.09.2017, p. 1063-1071.

Research output: Contribution to journalArticle

Dai, X, Gan, W, Li, X, Wang, S, Zhang, W, Huang, L, Liu, S, Zhong, Q, Guo, J, Zhang, J, Chen, T, Shimizu, K, Beca, F, Blattner, M, Vasudevan, D, Buckley, DL, Qi, J, Buser, L, Liu, P, Inuzuka, H, Beck, AH, Wang, LM, Wild, PJ, Garraway, LA, Rubin, MA, Barbieri, CE, Wong, KK, Muthuswamy, SK, Huang, J, Chen, Y, Bradner, JE & Wei, W 2017, 'Prostate cancer-Associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4', Nature Medicine, vol. 23, no. 9, pp. 1063-1071. https://doi.org/10.1038/nm.4378
Dai, Xiangpeng ; Gan, Wenjian ; Li, Xiaoning ; Wang, Shangqian ; Zhang, Wei ; Huang, Ling ; Liu, Shengwu ; Zhong, Qing ; Guo, Jianping ; Zhang, Jinfang ; Chen, Ting ; Shimizu, Kouhei ; Beca, Francisco ; Blattner, Mirjam ; Vasudevan, Divya ; Buckley, Dennis L. ; Qi, Jun ; Buser, Lorenz ; Liu, Pengda ; Inuzuka, Hiroyuki ; Beck, Andrew H. ; Wang, Liewei M ; Wild, Peter J. ; Garraway, Levi A. ; Rubin, Mark A. ; Barbieri, Christopher E. ; Wong, Kwok Kin ; Muthuswamy, Senthil K. ; Huang, Jiaoti ; Chen, Yu ; Bradner, James E. ; Wei, Wenyi. / Prostate cancer-Associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. In: Nature Medicine. 2017 ; Vol. 23, No. 9. pp. 1063-1071.
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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 M

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

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