title: Epigenetic reader BRD4 inhibition as a therapeutic strategy to suppress E2F2-cell cycle regulation circuit in liver cancer.
abstract: Deregulation of the epigenome component affects multiple pathways in the cancer phenotype since the epigenome acts at the pinnacle of the hierarchy of gene expression. Pioneering work over the past decades has highlighted that targeting enzymes or proteins involved in the epigenetic regulation is a valuable approach to cancer therapy. Very recent results demonstrated that inhibiting the epigenetic reader BRD4 has notable efficacy in diverse cancer types. We investigated the potential of BRD4 as a therapeutic target in liver malignancy. BRD4 was overexpressed in three different large cohort of hepatocellular carcinoma (HCC) patients as well as in liver cancer cell lines. BRD4 inhibition by JQ1 induced anti-tumorigenic effects including cell cycle arrest, cellular senescence, reduced wound healing capacity and soft agar colony formation in liver cancer cell lines. Notably, BRD4 inhibition caused MYC-independent large-scale gene expression changes in liver cancer cells. Serial gene expression analyses with SK-Hep1 liver cancer cells treated with JQ1 to delineate the key player of BRD4 inhibition identified E2F2 as the first line of downstream direct target of BRD4. Further experiments including chromatin immunoprecipitation (ChIP) assay and loss of function study confirmed E2F2 as key player of BRD4 inhibition. Overexpressed E2F2 is a crucial center of cell cycle regulation and high expression of E2F2 is significantly associated with poor prognosis of HCC patients. Our findings reveal BRD4-E2F2-cell cycle regulation as a novel molecular circuit in liver cancer and provide a therapeutic strategy and innovative insights for liver cancer therapies.
authors.affiliation: Konkuk University Medical Center, School of Medicine, Konkuk University, Seoul 143-701, Korea.
authors.forename: Seong Hwi
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Functional RNomics Research Center, College of Medicine, The Catholic University, Seoul 137-701, Korea.
authors.forename: Jung Woo
authors.initials: JW
authors.lastname: Eun
authors.affiliation: Konkuk University Medical Center, School of Medicine, Konkuk University, Seoul 143-701, Korea.
authors.forename: Sung Kyung
authors.initials: SK
authors.lastname: Choi
authors.affiliation: Functional RNomics Research Center, College of Medicine, The Catholic University, Seoul 137-701, Korea.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Konkuk University Medical Center, School of Medicine, Konkuk University, Seoul 143-701, Korea.
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
authors.affiliation: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Jeung-Whan
authors.initials: JW
authors.lastname: Han
authors.affiliation: Functional RNomics Research Center, College of Medicine, The Catholic University, Seoul 137-701, Korea.
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
authors.affiliation: Konkuk University Medical Center, School of Medicine, Konkuk University, Seoul 143-701, Korea.
authors.forename: Jueng Soo
authors.initials: JS
authors.lastname: You
mesh_terms: D001381:Azepines / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D050703:E2F2 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D044127:Epigenesis, Genetic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D050703:E2F2 Transcription Factor; D009687:Nuclear Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C493761:E2F2 protein, human
keywords: BET protein; E2F; JQ1; epigenetic components; hepatocellular carcinoma (HCC)