title: Suppression of BRD4 inhibits human hepatocellular carcinoma by repressing MYC and enhancing BIM expression.
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.
authors.affiliation: 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.
authors.forename: Gong-Quan
authors.initials: GQ
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Wen-Zhi
authors.initials: WZ
authors.lastname: Guo
authors.affiliation: Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.|The Hormel Institute, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Seng
authors.affiliation: 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.
authors.forename: Hua-Peng
authors.initials: HP
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Xiu-Xian
authors.initials: XX
authors.lastname: Ma
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Gong
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Tang
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Li
authors.affiliation: Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Li-Dong
authors.initials: LD
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Shui-Jun
authors.initials: SJ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology*; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D000072224:Bcl-2-Like Protein 11; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C489427:MYC protein, human
keywords: BIM; BRD4; HCC; JQ1; MYC