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

Publication ,  Journal Article
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; Qi, J ...
Published in: Nat Med
September 2017

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-3SPOP 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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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

September 2017

Volume

23

Issue

9

Start / End Page

1063 / 1071

Location

United States

Related Subject Headings

  • Ubiquitination
  • Triazoles
  • Transcription Factors
  • Thalidomide
  • Repressor Proteins
  • RNA-Binding Proteins
  • Protein Serine-Threonine Kinases
  • Prostatic Neoplasms
  • Nuclear Proteins
  • Molecular Targeted Therapy
 

Citation

APA
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ICMJE
MLA
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Dai, X., Gan, W., Li, X., Wang, S., Zhang, W., Huang, L., … Wei, W. (2017). Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nat Med, 23(9), 1063–1071. https://doi.org/10.1038/nm.4378
Dai, Xiangpeng, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, et al. “Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4.Nat Med 23, no. 9 (September 2017): 1063–71. https://doi.org/10.1038/nm.4378.
Dai X, Gan W, Li X, Wang S, Zhang W, Huang L, et al. Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nat Med. 2017 Sep;23(9):1063–71.
Dai, Xiangpeng, et al. “Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4.Nat Med, vol. 23, no. 9, Sept. 2017, pp. 1063–71. Pubmed, doi:10.1038/nm.4378.
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 L, Wild PJ, Garraway LA, Rubin MA, Barbieri CE, Wong K-K, Muthuswamy SK, Huang J, Chen Y, Bradner JE, Wei W. Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nat Med. 2017 Sep;23(9):1063–1071.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

September 2017

Volume

23

Issue

9

Start / End Page

1063 / 1071

Location

United States

Related Subject Headings

  • Ubiquitination
  • Triazoles
  • Transcription Factors
  • Thalidomide
  • Repressor Proteins
  • RNA-Binding Proteins
  • Protein Serine-Threonine Kinases
  • Prostatic Neoplasms
  • Nuclear Proteins
  • Molecular Targeted Therapy