title: SystematicIn VivoInactivation of Chromatin-Regulating Enzymes Identifies Setd2 as a Potent Tumor Suppressor in Lung Adenocarcinoma.
abstract: Chromatin-modifying genes are frequently mutated in human lung adenocarcinoma, but the functional impact of these mutations on disease initiation and progression is not well understood. Using a CRISPR-based approach, we systematically inactivated three of the most commonly mutated chromatin regulatory genes in two KrasG12D-driven mouse models of lung adenocarcinoma to characterize the impact of their loss. Targeted inactivation of SWI/SNF nucleosome-remodeling complex membersSmarca4(Brg1) orArid1ahad complex effects on lung adenocarcinoma initiation and progression. Loss of either Brg1 or Arid1a were selected against in early-stage tumors, but Brg1 loss continued to limit disease progression over time, whereas loss of Arid1a eventually promoted development of higher grade lesions. In contrast to these stage-specific effects, loss of the histone methyltransferase Setd2 had robust tumor-promoting consequences. Despite disparate impacts of Setd2 and Arid1a loss on tumor development, each resulted in a gene expression profile with significant overlap. Setd2 inactivation and subsequent loss of H3K36me3 led to the swift expansion and accelerated progression of both early- and late-stage tumors. However, Setd2 lossper sewas insufficient to overcome a p53-regulated barrier to malignant progression, nor establish the prometastatic cellular states that stochastically evolve during lung adenocarcinoma progression. Our study uncovers differential and context-dependent effects of SWI/SNF complex member loss, identifies Setd2 as a potent tumor suppressor in lung adenocarcinoma, and establishes model systems to facilitate further study of chromatin deregulation in lung cancer.Cancer Res; 77(7); 1719-29. ©2017 AACR.
authors.affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania.|Graduate Program in Cell and Molecular Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: David M
authors.initials: DM
authors.lastname: Walter
authors.affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Olivia S
authors.initials: OS
authors.lastname: Venancio
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Buza
authors.affiliation: Department of Genetics and Penn Genomics Analysis Core, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: John W
authors.initials: JW
authors.lastname: Tobias
authors.affiliation: Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Charuhas
authors.initials: C
authors.lastname: Deshpande
authors.affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: A Andrea
authors.initials: AA
authors.lastname: Gudiel
authors.affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kim-Kiselak
authors.affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Michelle
authors.initials: M
authors.lastname: Cicchini
authors.affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Yates
authors.affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania. dfeldser@upenn.edu.|Graduate Program in Cell and Molecular Biology, University of Pennsylvania, Philadelphia, Pennsylvania.|Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: David M
authors.initials: DM
authors.lastname: Feldser
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000517:prevention & control*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002843:Chromatin / Q000502:physiology*; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D004265:DNA Helicases / Q000502:physiology; D004268:DNA-Binding Proteins; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: C112476:ARID1A protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D016283:Proto-Oncogene Proteins p21(ras)