title: Loss of the deubiquitylase BAP1 alters class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors.
abstract: Histone deacetylases are important targets for cancer therapeutics, but their regulation is poorly understood. Our data show coordinated transcription of HDAC1 and HDAC2 in lung cancer cell lines, but suggest HDAC2 protein expression is cell-context specific. Through an unbiased siRNA screen we found that BRCA1-associated protein 1 (BAP1) regulates their expression, with HDAC2 reduced and HDAC1 increased in BAP1 depleted cells. BAP1 loss-of-function is increasingly reported in cancers including thoracic malignancies, with frequent mutation in malignant pleural mesothelioma. Endogenous HDAC2 directly correlates with BAP1 across a panel of lung cancer cell lines, and is downregulated in mesothelioma cell lines with genetic BAP1 inactivation. We find that BAP1 regulates HDAC2 by increasing transcript abundance, rather than opposing its ubiquitylation. Importantly, although total cellular HDAC activity is unaffected by transient depletion of HDAC2 or of BAP1 due to HDAC1 compensation, this isoenzyme imbalance sensitizes MSTO-211H cells to HDAC inhibitors. However, other established mesothelioma cell lines with low endogenous HDAC2 have adapted to become more resistant to HDAC inhibition. Our work establishes a mechanism by which BAP1 loss alters sensitivity of cancer cells to HDAC inhibitors. Assessment of BAP1 and HDAC expression may ultimately help identify patients likely to respond to HDAC inhibitors.
authors.affiliation: Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Sacco
authors.affiliation: Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Jenna
authors.initials: J
authors.lastname: Kenyani
authors.affiliation: Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Zohra
authors.initials: Z
authors.lastname: Butt
authors.affiliation: Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Carter
authors.affiliation: Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.|Current address: Cancer Stem Cell Biology, Agency for Science Technology and Research, Genome Institute of Singapore, Singapore.
authors.forename: Hui Yi
authors.initials: HY
authors.lastname: Chew
authors.affiliation: Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.|Current address: MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Liam P
authors.initials: LP
authors.lastname: Cheeseman
authors.affiliation: Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Darling
authors.affiliation: Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Denny
authors.affiliation: Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Urbé
authors.affiliation: Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clague
authors.affiliation: Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Judy M
authors.initials: JM
authors.lastname: Coulson
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D056284:Histone Deacetylase 1 / Q000096:biosynthesis*; D056464:Histone Deacetylase 2 / Q000096:biosynthesis / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D014158:Transcription, Genetic / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C400134:BAP1 protein, human; D056572:Histone Deacetylase Inhibitors; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
keywords: BRCA1-associated protein 1; MPM; histone deacetylase 2; stratified medicine; vorinostat