Androgen deprivation therapies for the hormone-dependent stages of prostate cancer have become so effective that new forms of chemoresistant tumors are emerging in clinical practice, and require new targeted therapies in the metastatic setting. Yet there are important gaps in our understanding of the relevant transcriptional networks driving this process. Progression from localized to metastatic castration resistant prostate cancer (mCRPC) occurs as a result of accumulated resistance mechanisms that develop upon sustained androgen receptor (AR) suppression. Critical to this progression is the plastic nature by which prostate tumor cells transition from epithelial to mesenchymal states (EMT).
Here, using prostate cancer cell lines with different AR composition, we systematically manipulated somatic proteins of the Bromodomain and ExtraTerminal (BET) family (BRD2, BRD3, and BRD4) to determine which BET proteins influence EMT. We used the TCGA repository to correlate the expression of individual BET genes with key EMT genes and determined biochemical recurrence in 414 patients and progression free survival in 488 patients.
We found that only BRD4—and not BRD2 or BRD3—regulates the expression of SNAI1 and SNAI2, and that the downregulation of these EMT transcription factors significantly increases E-cadherin expression. Furthermore, of the BET genes, only BRD4 correlates with survival outcomes in prostate cancer patients. Moreover, selective degradation of BRD4 protein with MZ1 ablates EMT (transcriptionally and morphologically) induced by TGFß signaling.
Many relapsed/refractory tumors share a neuroendocrine transcriptional signature that had been relatively rare until highly successful antiandrogen drugs like abiraterone and enzalutamide came into widespread use. New therapeutic targets must therefore be developed. Our results identify key EMT genes regulated by BRD4, and offers a novel druggable target to treat mCRPC. BRD4-selective protein degraders offer a promising next generation approach to treat the emerging forms of chemoresistance in advanced prostate cancer.
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We thank Dr. Alessio Ciulli for providing MZ1 and the Boston University-Boston Medical Center Flow Cytometry and Cellular Imaging Core Facilities for technical assistance. J. Shafran is supported by a T32 training grant, ‘Research Training in Immunology’ from NIAID (5T32AI007309-30, PI Kepler). This study was supported by grants from the National Institutes of Health (DK090455, U01CA182898, R01CA222170; GV Denis; T32AI007309; TB Kepler) and the Shipley Prostate Cancer Research Center. The funders had no role in study design, data collection and analysis, preparation of the manuscript or decision to publish.
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Shafran, J.S., Jafari, N., Casey, A.N. et al. BRD4 regulates key transcription factors that drive epithelial–mesenchymal transition in castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 24, 268–277 (2021). https://doi.org/10.1038/s41391-020-0246-y
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