Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Cancer Cell. 2016 Sep 12;30(3):459-473. doi: 10.1016/j.ccell.2016.08.001.
Histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits in subtypes of hematological malignancies. However, the efficacy of HDAC inhibitors in solid tumors remains uncertain. This study takes breast cancer as a model to understand mechanisms accounting for limited response of HDAC inhibitors in solid tumors and to seek combination solutions. We discover that feedback activation of leukemia inhibitory factor receptor (LIFR) signaling in breast cancer limits the response to HDAC inhibition. Mechanistically, HDAC inhibition increases histone acetylation at the LIFR gene promoter, which recruits bromodomain protein BRD4, upregulates LIFR expression, and activates JAK1-STAT3 signaling. Importantly, JAK1 or BRD4 inhibition sensitizes breast cancer to HDAC inhibitors, implicating combination inhibition of HDAC with JAK1 or BRD4 as potential therapies for breast cancer.
组蛋白去乙酰化酶 (HDAC) 抑制剂在血液系统恶性肿瘤的某些亚型中显示出临床益处。然而，HDAC 抑制剂在实体瘤中的疗效仍不确定。本研究以乳腺癌为模型，旨在了解导致 HDAC 抑制剂在实体瘤中反应有限的机制，并寻求联合解决方案。我们发现，乳腺癌中白血病抑制因子受体 (LIFR) 信号的反馈激活限制了对 HDAC 抑制的反应。从机制上讲，HDAC 抑制会增加 LIFR 基因启动子处的组蛋白乙酰化，从而招募溴结构域蛋白 BRD4，上调 LIFR 表达，并激活 JAK1-STAT3 信号。重要的是，JAK1 或 BRD4 抑制使乳腺癌对 HDAC 抑制剂敏感，这表明 HDAC 与 JAK1 或 BRD4 的联合抑制可能是治疗乳腺癌的一种潜在疗法。
