title: SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer.
abstract: Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16INK4aand p21CIP1atranscription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators, including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage, and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that prosenescence therapies could be employed against SWI/SNF-mutated cancers.
authors.affiliation: MRC Clinical Sciences Centre (CSC), London W12 0NN, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Luca
authors.initials: L
authors.lastname: Tordella
authors.affiliation: MRC Clinical Sciences Centre (CSC), London W12 0NN, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Khan
authors.affiliation: Division of Molecular Oncology of Solid Tumours, Department of Internal Medicine I, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Hohmeyer
authors.affiliation: MRC Clinical Sciences Centre (CSC), London W12 0NN, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Banito
authors.affiliation: Division of Molecular Oncology of Solid Tumours, Department of Internal Medicine I, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Klotz
authors.affiliation: MRC Clinical Sciences Centre (CSC), London W12 0NN, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Selina
authors.initials: S
authors.lastname: Raguz
authors.affiliation: MRC Clinical Sciences Centre (CSC), London W12 0NN, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Nadine
authors.initials: N
authors.lastname: Martin
authors.affiliation: MRC Clinical Sciences Centre (CSC), London W12 0NN, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Gopuraja
authors.initials: G
authors.lastname: Dhamarlingam
authors.affiliation: MRC Clinical Sciences Centre (CSC), London W12 0NN, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carroll
authors.affiliation: Developmental Biology and Cancer Programme, Birth Defects Research Centre, University College London Institute of Child Health, London WC1N 1EH, United Kingdom.
authors.forename: José Mario
authors.initials: JM
authors.lastname: González Meljem
authors.affiliation: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors.forename: Sumit
authors.initials: S
authors.lastname: Deswal
authors.affiliation: Developmental Biology and Cancer Programme, Birth Defects Research Centre, University College London Institute of Child Health, London WC1N 1EH, United Kingdom.
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Martínez-Barbera
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain.|Biomedical Research Institute I+12, University Hospital 12 de Octubre, 28041 Madrid, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Escudero
authors.affiliation: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Division of Molecular Oncology of Solid Tumours, Department of Internal Medicine I, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.affiliation: MRC Clinical Sciences Centre (CSC), London W12 0NN, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Jesús
authors.initials: J
authors.lastname: Gil
mesh_terms: D000818:Animals; D001081:Apyrase / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: C497837:ARID1B protein, human; C000612244:Arid1b protein, mouse; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D001081:Apyrase
keywords: ARID1B; ENTPD7; SWI/SNF; cancer; dNTP metabolism; p53; senescence