BRD4 regulates key transcription factors that drive epithelial-mesenchymal transition in castration-resistant prostate cancer.

Autor: Shafran JS; Boston University-Boston Medical Center Cancer Center, Boston, MA, 02118, USA.; Department of Molecular and Translational Medicine, Boston University School of Medicine, Boston, MA, 02118, USA., Jafari N; Boston University-Boston Medical Center Cancer Center, Boston, MA, 02118, USA., Casey AN; Boston University-Boston Medical Center Cancer Center, Boston, MA, 02118, USA.; Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA., Győrffy B; Department of Bioinformatics and 2nd Department of Pediatrics, Semmelweis University, Budapest, 1094, Hungary.; TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Budapest, 1117, Hungary., Denis GV; Boston University-Boston Medical Center Cancer Center, Boston, MA, 02118, USA. gdenis@bu.edu.; Department of Molecular and Translational Medicine, Boston University School of Medicine, Boston, MA, 02118, USA. gdenis@bu.edu.; Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA. gdenis@bu.edu.
Jazyk: angličtina
Zdroj: Prostate cancer and prostatic diseases [Prostate Cancer Prostatic Dis] 2021 Mar; Vol. 24 (1), pp. 268-277. Date of Electronic Publication: 2020 Jul 21.
DOI: 10.1038/s41391-020-0246-y
Abstrakt: 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 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.
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.
Databáze: MEDLINE
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