Shukla Shipra, Li Dan, Cho Woo Hyun, Schoeps Dana M, Nguyen Holly M, Conner Jennifer L, Roskes Marjorie L, Tehim Anisha, Bayshtok Gabriella, Pachai Mohini R, Yan Juan, Teri Nicholas A, Campeau Eric, Attwell Sarah, Trojer Patrick, Ostrovnaya Irina, Gopalan Anuradha, Khurana Ekta, Corey Eva, Chi Ping, Chen Yu
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America.
Department of Urology, University of Washington, Seattle, United States of America.
J Clin Invest. 2025 Jun 24;135(16). doi: 10.1172/JCI180378.
A subgroup (~20-30%) of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by two GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlates with adverse clinical outcomes to androgen receptor signaling inhibitor treatment and shorter overall survival. Bromo- and extra-terminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, while 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.
约20%-30%的去势抵抗性前列腺癌（CRPC）亚群异常表达由两种胃肠道（GI）谱系限制性转录因子HNF1A和HNF4G调控的胃肠道转录组。在本研究中，我们发现CRPC中胃肠道转录组的表达与雄激素受体信号抑制剂治疗的不良临床结局及较短的总生存期相关。在多个CRPC模型中，包括细胞系、患者来源的类器官和患者来源的异种移植模型，溴结构域和额外末端结构域抑制剂（BETi）下调了HNF1A、HNF4G和胃肠道转录组，而雄激素受体（AR）和雄激素依赖性转录组基本未受影响。因此，BETi选择性抑制了胃肠道转录组阳性的前列腺癌临床前模型的生长。从机制上讲，BETi全局抑制增强子处的BRD4结合，包括AR和HNF4G结合的增强子，同时选择性地干扰基因表达。在BETi存在的情况下恢复HNF4G表达可挽救靶基因表达，但不能挽救BRD4结合。这表明抑制主转录因子的表达是BETi选择性转录效应的基础。
