科学家们使用多梳蛋白的药理学抑制剂来恢复肿瘤抑制基因的表达并阻止癌症增殖和侵袭。这种方法的一个主要限制是关键转录激活因子，例如 TP53 和 BAF SWI/SNF，在癌症中经常发生突变。多梳靶向疗法在实体癌（包括三阴性乳腺癌（TNBC））中的临床效果不佳，可能会阻碍表观遗传单一疗法的进一步发展。在这里，我们使用合成读取器驱动器 (SRA) 进行表观基因组驱动，该合成器驱动器结合多梳染色质中的三甲基化组蛋白 H3 赖氨酸 27 并调节核心转录激活子。在表达 SRA 的 TNBC BT-549 细胞中，122 个基因上调 ≥2 倍，包括与细胞死亡、细胞周期停滞和迁移抑制有关的基因。表达 SRA 的球体在基质胶中显示尺寸减小且侵袭丧失。因此，将招募调节因子的介体靶向沉默的染色质可以激活肿瘤抑制因子并刺激抗癌表型，并且进一步开发强大的基因调节因子可能使 TNBC 患者受益。版权所有 2023，Mary Ann Liebert, Inc.，出版商。

Scientists have used pharmacological inhibitors of polycomb proteins to restore the expression of tumor suppressor genes and stop cancer proliferation and invasion. A major limitation of this approach is that key transcriptional activators, such as TP53 and BAF SWI/SNF, are often mutated in cancer. Poor clinical results for polycomb-targeting therapies in solid cancers, including triple-negative breast cancer (TNBC), could discourage the further development of epigenetic monotherapies. Here, we performed epigenome actuation with a synthetic reader-actuator (SRA) that binds trimethylated histone H3 lysine 27 in polycomb chromatin and modulates core transcriptional activators. In SRA-expressing TNBC BT-549 cells, 122 genes become upregulated ≥2-fold, including the genes involved in cell death, cell cycle arrest, and migration inhibition. The SRA-expressing spheroids showed reduced size in Matrigel and loss of invasion. Therefore, targeting Mediator-recruiting regulators to silenced chromatin can activate tumor suppressors and stimulate anti-cancer phenotypes, and further development of robust gene regulators might benefit TNBC patients.Copyright 2023, Mary Ann Liebert, Inc., publishers.