BET inhibitors reduce tumor growth in preclinical models of gastrointestinal gene signature-positive castration-resistant prostate cancer Journal Article
| Authors: | Shukla, S.; Li, D.; Cho, W. H.; Schoeps, D. M.; Nguyen, H. M.; Conner, J. L.; Roskes, M. L.; Tehim, A.; Bayshtok, G.; Pachai, M. R. |
| Article Title: | BET inhibitors reduce tumor growth in preclinical models of gastrointestinal gene signature-positive castration-resistant prostate cancer |
| Abstract: | A subgroup (~20%-30%) of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by 2 GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlated with adverse clinical outcomes to androgen receptor (AR) signaling inhibitor treatment and shorter overall survival. Bromo- and extraterminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, whereas AR and the androgen-dependent transcriptome were largely spared. Accordingly, BETi selectively inhibited growth of GI transcriptome-positive preclinical models of prostate cancer. Mechanistically, BETi inhibited BRD4 binding at enhancers globally, including both AR and HNF4G bound enhancers, while gene expression was selectively perturbed. Restoration of HNF4G expression in the presence of BETi rescued target gene expression without rescuing BRD4 binding. This suggests that inhibition of master transcription factors expression underlies the selective transcriptional effects of BETi. This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine |
| Keywords: | genetics; cell cycle protein; mouse; animal; metabolism; animals; cell cycle proteins; mice; neoplasm proteins; transcription factor; drug effect; drug screening; pathology; xenograft model antitumor assays; cell line, tumor; oncology; transcription factors; gene expression regulation; gene expression regulation, neoplastic; epigenetics; tumor protein; tumor cell line; androgen receptor; receptors, androgen; drug therapy; transcriptome; castration resistant prostate cancer; cell biology; humans; human; male; prostatic neoplasms, castration-resistant; hepatocyte nuclear factor 4; brd4 protein, human; bromodomain containing proteins; bromodomain containing protein |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 135 |
| Issue: | 16 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2025-01-01 |
| Language: | English |
| DOI: | 10.1172/jci180378 |
| PUBMED: | 40553565 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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