Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4
The bromodomain and extra-terminal (BET) family of proteins, comprised of four members including BRD2, BRD3, BRD4 and the testis-specific isoform BRDT, largely function as transcriptional co-activators 1–3 and play critical roles in various cellular processes, including cell cycle, apoptosis, migration and invasion 4,5. As such, BET proteins enhance the oncogenic functions of major cancer drivers by either elevating their expression such as c-Myc in leukemia 6,7 or by promoting transcriptional activities of oncogenic factors such as AR and ERG in the prostate cancer setting 8. Pathologically, BET proteins are frequently overexpressed and clinically linked to various types of human cancers 5,9,10, therefore pursued as attractive therapeutic targets for selective inhibition in patients. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed 11,12 and shown promising outcomes in early clinical trials. Despite resistance to BET inhibitor has been documented in pre-clinical models 13–15 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 destruction of BET proteins, leading to their elevated abundance in SPOP-deficient prostate cancer. As a result, prostate cancer cells and prostate cancer patient-derived organoids 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 by negatively controlling BET protein stability, and also provide a molecular mechanism for BET inhibitor resistance in prostate cancer patients bearing SPOP mutations.
[…] Genomic alterations were identified by querying genomic data from Prostate Adenocarcinoma dataset of TCGA. Comprehensive data of 485 prostate adenocarcinoma cases were retrieved from the TCGA database (http://cancergenome.nih.gov/) regarding RNAseq gene expression (Illumina HiSeq RNASeqV2 Level 126.96.36.199). Annotations regarding SPOP mutation status were obtained from cBioPortal (http://www.cbioportal.org/) on the 06/29/2015 . BRD4 mRNA expression levels were dichotomized into low and high expression categories using a model for classification based on finite normal mixture modeling (mclust 5.1 package, R 3.2.2). Differential gene expression was performed using two-class paired significance of microarray data (SAM 2.0 package, R 3.2.2) and genes considered differentially expressed when FDR < 0.05. […]
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