title: HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer.
abstract: Mutation of p53 is a frequent genetic lesion in pancreatic cancer being an unmet clinical challenge. Mutants of p53 have lost the tumour-suppressive functions of wild type p53. In addition, p53 mutants exert tumour-promoting functions, qualifying them as important therapeutic targets. Here, we show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine pancreatic cancer cells. Our data reveal that the inhibition of these HDACs with small molecule HDAC inhibitors (HDACi), as well as the specific genetic elimination of HDAC1 and HDAC2, reduce the expression of mutant p53 mRNA and protein levels. We further show that HDAC1, HDAC2 and MYC directly bind to the TP53 gene and that MYC recruitment drops upon HDAC inhibitor treatment. Therefore, our results illustrate a previously unrecognized class I HDAC-dependent control of the TP53 gene and provide evidence for a contribution of MYC. A combined approach targeting HDAC1/HDAC2 and MYC may present a novel and molecularly defined strategy to target mutant p53 in pancreatic cancer.
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Stojanovic
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: Z
authors.initials: Z
authors.lastname: Hassan
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wirth
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Wenzel
authors.affiliation: Department of Toxicology, University of Mainz Medical Center, Mainz, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Beyer
authors.affiliation: Institute of Biochemistry and Biophysics/Center for Molecular Biomedicine (CMB), Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schäfer
authors.affiliation: Institute of Biochemistry and Biophysics/Center for Molecular Biomedicine (CMB), Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Brand
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kroemer
authors.affiliation: Molecular and Cellular Oncology/ENT, University Medical Center Mainz, Mainz, Germany.
authors.forename: R H
authors.initials: RH
authors.lastname: Stauber
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: R M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Arlt
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Chemistry I, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sellmer
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Chemistry I, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Mahboobi
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.|German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Rad
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.|Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Reichert
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.|German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Saur
authors.affiliation: Department of Toxicology, University of Mainz Medical Center, Mainz, Germany.
authors.forename: O H
authors.initials: OH
authors.lastname: Krämer
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.|German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D056572:Histone Deacetylase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2