Li Gong-Quan, Guo Wen-Zhi, Zhang Yi, Seng Jing-Jing, Zhang Hua-Peng, Ma Xiu-Xian, Zhang Gong, Li Jie, Yan Bing, Tang Hong-Wei, Li Shan-Shan, Wang Li-Dong, Zhang Shui-Jun
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Oncotarget. 2016 Jan 19;7(3):2462-74. doi: 10.18632/oncotarget.6275.
Bromodomain 4 (BRD4) is an epigenetic regulator that, when inhibited, has anti-cancer effects. In this study, we investigated whether BRD4 could be a target for treatment of human hepatocellular carcinoma (HCC). We show that BRD4 is over-expressed in HCC tissues. Suppression of BRD4, either by siRNA or using JQ1, a pharmaceutical BRD4 inhibitor, reduced cell growth and induced apoptosis in HCC cell lines while also slowing HCC xenograft tumor growth in mice. JQ1 treatment induced G1 cell cycle arrest by repressing MYC expression, which led to the up-regulation of CDKN1B (P27). JQ1 also de-repressed expression of the pro-apoptotic BCL2L11 (BIM). Moreover, siRNA knockdown of BIM attenuated JQ1-triggered apoptosis in HCC cells, suggesting an essential role for BIM in mediating JQ1 anti-HCC activity.
溴结构域 4（BRD4）是一种表观遗传调节因子，受到抑制时具有抗癌作用。在本研究中，我们调查了 BRD4 是否可作为治疗人类肝细胞癌（HCC）的靶点。我们发现 BRD4 在 HCC 组织中过表达。通过 siRNA 或使用药物性 BRD4 抑制剂 JQ1 抑制 BRD4，可减少 HCC 细胞系中的细胞生长并诱导细胞凋亡，同时还能减缓小鼠体内 HCC 异种移植肿瘤的生长。JQ1 处理通过抑制 MYC 表达诱导 G1 期细胞周期停滞，这导致 CDKN1B（P27）上调。JQ1 还去抑制了促凋亡蛋白 BCL2L11（BIM）的表达。此外，BIM 的 siRNA 敲低减弱了 JQ1 触发的 HCC 细胞凋亡，表明 BIM 在介导 JQ1 的抗 HCC 活性中起重要作用。
