溴结构域和末端外结构域 (BET) 家族蛋白作为乙酰化赖氨酸残基的主要读取器，在细胞增殖和分化中发挥至关重要的作用。 BET 蛋白的失调与肿瘤发生有关，使其成为重要的治疗靶点。 BET 溴结构域 (BD) 抑制剂和 BET 靶向降解剂已被开发用于抑制 BET 蛋白。在这项研究中，我们发现 BET 抑制剂 MS645 在三阴性乳腺癌 (TNBC) 细胞中表现出比 BET 降解剂（包括 ARV771、AT1、MZ1 和 dBET1）更优异的抗增殖活性。 MS645 处理导致 BET、MED1 和 RNA 聚合酶 II 从 E2F1-3 启动子上解离，从而抑制 E2F1-3 转录并随后抑制 TNBC 中的细胞生长。相比之下，虽然 ARV771 从染色质中取代了 BET 蛋白，但它并没有显着改变 E2F1-3 的表达。从机制上讲，ARV771 在蛋白质水平上诱导 BRD4 耗竭，从而显着增加 EGR1 表达。 EGR1 的升高随后将 septin 2 和 septin 9 募集至 E2F1-3 启动子，增强 E2F1-3 转录并促进体外和体内细胞增殖率。我们的研究结果为 BET 抑制的差异机制提供了宝贵的见解，并强调了开发 BET 靶向分子作为 TNBC 治疗策略的潜力。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

The bromodomain and extraterminal domain (BET) family proteins serve as primary readers of acetylated lysine residues and play crucial roles in cell proliferation and differentiation. Dysregulation of BET proteins has been implicated in tumorigenesis, making them important therapeutic targets. BET-bromodomain (BD) inhibitors and BET-targeting degraders have been developed to inhibit BET proteins. In this study, we found that the BET inhibitor MS645 exhibited superior antiproliferative activity than BET degraders including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer (TNBC) cells. Treatment with MS645 led to the dissociation of BETs, MED1 and RNA polymerase II from the E2F1-3 promoter, resulting in the suppression of E2F1-3 transcription and subsequent inhibition of cell growth in TNBC. In contrast, while ARV771 displaced BET proteins from chromatin, it did not significantly alter E2F1-3 expression. Mechanistically, ARV771 induced BRD4 depletion at protein level, which markedly increased EGR1 expression. This elevation of EGR1 subsequently recruited septin 2 and septin 9 to E2F1-3 promoters, enhancing E2F1-3 transcription and promoting cell proliferation rate in vitro and in vivo. Our findings provide valuable insights into differential mechanisms of BET inhibition and highlight potential of developing BET-targeting molecules as therapeutic strategies for TNBC.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.