Suppression of BRD4 inhibits human hepatocellular carcinoma by repressing MYC and enhancing BIM expression
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Gong-Quan Li1,2,*, Wen-Zhi Guo1,*, Yi Zhang3,4, Jing-Jing Seng5, Hua-Peng Zhang2, Xiu-Xian Ma1, Gong Zhang1, Jie Li1, Bing Yan2, Hong-Wei Tang2, Shan-Shan Li6, Li-Dong Wang7 and Shui-Jun Zhang1,2
1 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
2 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
3 Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
4 The Hormel Institute, University of Minnesota, Minneapolis, MN, USA
5 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
6 Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
7 Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
* These authors have contributed equally to this work
Shui-Jun Zhang, email:
Keywords: HCC, JQ1, BRD4, BIM, MYC
Received: June 29, 2015 Accepted: October 01, 2015 Published: November 12, 2015
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.
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