Suppression of BRD4 inhibits human hepatocellular carcinoma by repressing MYC and enhancing BIM expression

Gong-Quan Li; Wen-Zhi Guo; Yi Zhang; Jing-Jing Seng; Hua-Peng Zhang; Xiu-Xian Ma; Gong Zhang; Jie Li; Bing Yan; Hong-Wei Tang; Shan-Shan Li; Li-Dong Wang; Shui-Jun Zhang

doi:10.18632/oncotarget.6275

Suppression of BRD4 inhibits human hepatocellular carcinoma by repressing MYC and enhancing BIM expression

Oncotarget. 2016 Jan 19;7(3):2462-74. doi: 10.18632/oncotarget.6275.

Authors

Gong-Quan Li^{1

2}, Wen-Zhi Guo¹, Yi Zhang^{3

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, Shui-Jun Zhang^{1

2}

Affiliations

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.

Abstract

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.

Keywords: BIM; BRD4; HCC; JQ1; MYC.

MeSH terms

Animals
Apoptosis / drug effects
Azepines / pharmacology*
Bcl-2-Like Protein 11 / genetics
Bcl-2-Like Protein 11 / metabolism*
Blotting, Western
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Carcinoma, Hepatocellular / prevention & control*
Cell Cycle Proteins
Cell Proliferation / drug effects
Chromatin Immunoprecipitation
Flow Cytometry
Gene Expression Regulation, Neoplastic / drug effects*
Humans
Immunoenzyme Techniques
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Liver Neoplasms / prevention & control*
Mice
Nuclear Proteins / antagonists & inhibitors*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism*
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors / antagonists & inhibitors*
Transcription Factors / genetics
Transcription Factors / metabolism
Triazoles / pharmacology*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

(+)-JQ1 compound
Azepines
BRD4 protein, human
Bcl-2-Like Protein 11
Cell Cycle Proteins
MYC protein, human
Nuclear Proteins
Proto-Oncogene Proteins c-myc
RNA, Messenger
RNA, Small Interfering
Transcription Factors
Triazoles