Journal Article

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

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

2017

Overview

Recurrent mutations in SPOP -encoding a Cullin 3-based E3 ubiquitin ligase- in prostate cancer disrupt the recognition and degradation of ubiquitination substrates, including BET proteins. Consequently, stability of BET proteins is enhanced and this increases the resistance to BET inhibitors in SPOP -mutant prostate tumors. These results, together with those in Janouskova et al. and Zhang et al ., uncover a novel non genetic mechanism of resistance to BET inhibition involving cancer type-specific mutations in SPOP , and support the evaluation of SPOP mutations to inform the administration of BET inhibitors in the clinic. 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 1 , 2 , 3 and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion 4 , 5 . BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia 6 , 7 , or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer 8 . Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer 5 , 9 , 10 ; 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 11 , 12 and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models 13 , 14 , 15 , 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/51 / 13/95 / 42/109 / 631/67/1059/602 / 631/80/458/582 / 631/80/474/2073 / 631/80/86 / 82/29 / 82/58 / 82/83 / 96/95 / Abundance / Apoptosis / Azepines / Benzodiazepines / Bet protein / Biomedicine / c-Myc protein / Cancer Research / Cell cycle / Cell Proliferation / Clinical trials / Cullin / Cullin Proteins / Degradation / Drug resistance / Drug Resistance, Neoplasm - genetics / Drug therapy / Gene mutation / Genetic aspects / HEK293 Cells / HeLa Cells / Humans / Immunoblotting / Immunoprecipitation / Infectious Diseases / Inhibitor drugs / Inhibitors / letter / Leukemia / Male / Medical research / Metabolic Diseases / Molecular Medicine / Molecular modelling / Molecular Targeted Therapy / Mutation / Myc protein / Neurosciences / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Organoids / Physiological aspects / Prostate cancer / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - genetics / Prostatic Neoplasms - metabolism / Protein-Serine-Threonine Kinases / Proteins / Repressor Proteins - genetics / RNA-Binding Proteins / Thalidomide - analogs & derivatives / Transcription / Transcription Factors - metabolism / Triazoles / Tumor cell lines / Ubiquitination