Background 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). Methods 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. Results We found that only BRD4-and
not BRD2 or BRD3-regulates the expression ofSNAI1andSNAI2, and that the downregulation
of these EMT transcription factors significantly increases E-cadherin expression.
Furthermore, of the BET genes, onlyBRD4correlates with survival outcomes in prostate
cancer patients. Moreover, selective degradation of BRD4 protein with MZ1 ablates
EMT (transcriptionally and morphologically) induced by TGFss signaling. Conclusions
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.
