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.