title: Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4- and MYC-dependent manner.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a particularly dismal prognosis. Histone deacetylases (HDAC) are epigenetic modulators whose activity is frequently deregulated in various cancers including PDAC. In particular, class-I HDACs (HDAC 1, 2, 3 and 8) have been shown to play an important role in PDAC. In this study, we investigated the effects of the class I-specific HDAC inhibitor (HDACi) 4SC-202 in multiple PDAC cell lines in promoting tumor cell differentiation. We show that 4SC-202 negatively affects TGFβ signaling and inhibits TGFβ-induced epithelial-to-mesenchymal transition (EMT). Moreover, 4SC-202 markedly induced p21 (CDKN1A) expression and significantly attenuated cell proliferation. Mechanistically, genome-wide studies revealed that 4SC-202-induced genes were enriched for Bromodomain-containing Protein-4 (BRD4) and MYC occupancy. BRD4, a well-characterized acetyllysine reader, has been shown to play a major role in regulating transcription of selected subsets of genes. Importantly, BRD4 and MYC are essential for the expression of a subgroup of genes induced by class-I HDACi. Taken together, our study uncovers a previously unknown role of BRD4 and MYC in eliciting the HDACi-mediated induction of a subset of genes and provides molecular insight into the mechanisms of HDACi action in PDAC.
authors.affiliation: Department of General, Visceral and Pediatric Surgery, Göttingen Center for Molecular Biosciences, University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
authors.forename: Vivek Kumar
authors.initials: VK
authors.lastname: Mishra
authors.affiliation: Department of General, Visceral and Pediatric Surgery, Göttingen Center for Molecular Biosciences, University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wegwitz
authors.affiliation: Department of General, Visceral and Pediatric Surgery, Göttingen Center for Molecular Biosciences, University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
authors.forename: Robyn Laura
authors.initials: RL
authors.lastname: Kosinsky
authors.affiliation: Department of General, Visceral and Pediatric Surgery, Göttingen Center for Molecular Biosciences, University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
authors.forename: Madhobi
authors.initials: M
authors.lastname: Sen
authors.affiliation: 4SC AG, Am Klopferspitz 19a, 82152 Planegg-Martinsried, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Baumgartner
authors.affiliation: 4SC AG, Am Klopferspitz 19a, 82152 Planegg-Martinsried, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Wulff
authors.affiliation: German Consortium for Translational Cancer Research (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
authors.affiliation: Department of Pathology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schildhaus
authors.affiliation: Department of General, Visceral and Pediatric Surgery, Göttingen Center for Molecular Biosciences, University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
authors.forename: Zeynab
authors.initials: Z
authors.lastname: Najafova
authors.affiliation: Department of General, Visceral and Pediatric Surgery, Göttingen Center for Molecular Biosciences, University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Kari
authors.affiliation: 4SC AG, Am Klopferspitz 19a, 82152 Planegg-Martinsried, Germany.
authors.forename: Hella
authors.initials: H
authors.lastname: Kohlhof
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hessmann
authors.affiliation: Department of General, Visceral and Pediatric Surgery, Göttingen Center for Molecular Biosciences, University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018797:Cell Cycle Proteins; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C489427:MYC protein, human; C000614036:domatinostat; C110550:HDAC1 protein, human