title: Epigenetic blockade of neoplastic transformation by bromodomain and extra-terminal (BET) domain protein inhibitor JQ-1.
abstract: The neoplastic transformation of cells and inflammation are processes that contribute to tumor initiation. Recently, emerging evidence has suggested that epigenetic alterations are also implicated in the early stages of carcinogenesis. Therefore, potent small molecules targeting epigenetic regulators have been developed as novel cancer therapeutic and preventive strategies. Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that play key roles at the interface between chromatin modification and transcriptional regulation. In this study, we investigated the effect of the BET inhibitor JQ-1 on malignant transformation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin epidermal JB6 P+ cells. Treatment with JQ-1 effectively impaired TPA-induced colony formation in vitro. At the molecular level, the expression of several key TPA-induced pro-survival and pro-proliferative genes (Bcl2, Cyclin D1, and c-Myc) decreased rapidly after BET inhibition. In addition, JQ-1 treatment attenuated the activation of inflammatory NF-κB signaling triggered by TPA. Luciferase reporter assays using plasmids carrying different elements from the COX2 or IL6 promoters demonstrated that JQ-1 does not directly inhibit interactions between NF-κB and its binding sequence; rather, it affects CRE-element-associated transcriptional enhancement. Through siRNA gene silencing, we found that JQ-1 inhibits the p300-dependent transcriptional activation of COX2, which correlates with the results of the luciferase assay. Chromatin immunoprecipitation assays showed that TPA elevated H3K27Ac enrichment in the COX2 promoter region, which is mediated by p300, and Brd4. JQ-1 treatment did not change H3K27Ac levels but decreased the recruitment of Brd4 and RNA Polymerase II. Collectively, our study reveals that the BET inhibitor JQ-1 exerts potent anti-cancer and anti-inflammatory effects by interfering with the core transcriptional program of neoplastic transformation.
authors: Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA.
authors: Chengyue
authors: C
authors: Zhang
authors: Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA.
authors: Zheng-Yuan
authors: ZY
authors: Su
authors: Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, China.
authors: Ling
authors: L
authors: Wang
authors: Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA.
authors: Limin
authors: L
authors: Shu
authors: Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA.
authors: Yuqing
authors: Y
authors: Yang
authors: Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA.
authors: Yue
authors: Y
authors: Guo
authors: Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA.
authors: Douglas
authors: D
authors: Pung
authors: Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, UK.
authors: Chas
authors: C
authors: Bountra
authors: Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA. Electronic address: KongT@pharmacy.rutgers.edu.
authors: Ah-Ng
authors: AN
authors: Kong
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000633:toxicity; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D001381:Azepines; D002273:Carcinogens; D051546:Cyclooxygenase 2; D050881:E1A-Associated p300 Protein; D006657:Histones; D009687:Nuclear Proteins; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C554292:12-O-tetradecanoylphorbol-1,3-acetate; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C077623:Ptgs2 protein, mouse; C494361:Ep300 protein, mouse
keywords: Brd4; Bromodomain; JQ-1; NF-κB; Neoplastic transformation