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.
MeSH terms
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Azepines / pharmacology*
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Azepines / therapeutic use
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Blotting, Western
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cell Survival
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Drug Resistance, Neoplasm*
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Gene Expression Profiling
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Humans
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Immunoprecipitation
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Male
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Mechanistic Target of Rapamycin Complex 1
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Molecular Targeted Therapy
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Multiprotein Complexes / drug effects
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Multiprotein Complexes / metabolism
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Mutation
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / drug effects
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / metabolism
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Proteasome Endopeptidase Complex / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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RNA-Binding Proteins / antagonists & inhibitors
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RNA-Binding Proteins / drug effects
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RNA-Binding Proteins / metabolism
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Repressor Proteins / genetics*
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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TOR Serine-Threonine Kinases / drug effects
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TOR Serine-Threonine Kinases / metabolism
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / drug effects
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Transcription Factors / metabolism
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Triazoles / pharmacology*
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Triazoles / therapeutic use
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rac1 GTP-Binding Protein / genetics*
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rac1 GTP-Binding Protein / metabolism
Substances
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(+)-JQ1 compound
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Azepines
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BRD2 protein, human
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BRD3 protein, human
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BRD4 protein, human
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Cell Cycle Proteins
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Multiprotein Complexes
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Nuclear Proteins
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RAC1 protein, human
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RNA-Binding Proteins
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Repressor Proteins
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SPOP protein, human
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Transcription Factors
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Triazoles
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Mechanistic Target of Rapamycin Complex 1
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Proteasome Endopeptidase Complex
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rac1 GTP-Binding Protein