title: Gene amplification of the histone methyltransferase SETDB1 contributes to human lung tumorigenesis.
abstract: Disruption of the histone modification patterns is one of the most common features of human tumors. However, few genetic alterations in the histone modifier genes have been described in tumorigenesis. Herein we show that the histone methyltransferase SETDB1 undergoes gene amplification in non-small and small lung cancer cell lines and primary tumors. The existence of additional copies of the SETDB1 gene in these transformed cells is associated with higher levels of the corresponding mRNA and protein. From a functional standpoint, the depletion of SETDB1 expression in amplified cells reduces cancer growth in cell culture and nude mice models, whereas its overexpression increases the tumor invasiveness. The increased gene dosage of SETDB1 is also associated with enhanced sensitivity to the growth inhibitory effect mediated by the SETDB1-interfering drug mithramycin. Overall, the findings identify SETDB1 as a bona fide oncogene undergoing gene amplification-associated activation in lung cancer and suggest its potential for new therapeutic strategies.
authors.affiliation: Cancer Epigenetics and Biology Progrm (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez-Paredes
authors.affiliation: Cancer Epigenetics and Biology Progrm (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Martinez de Paz
authors.affiliation: Cancer Epigenetics and Biology Progrm (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Simó-Riudalbas
authors.affiliation: Cancer Epigenetics and Biology Progrm (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Sayols
authors.affiliation: Cancer Epigenetics and Biology Progrm (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Moutinho
authors.affiliation: Cancer Epigenetics and Biology Progrm (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Moran
authors.affiliation: Translational Research Laboratory, IDIBELL-Institut Catala d'Oncologia, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: 1] Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain [2] Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Vázquez-Cedeira
authors.affiliation: 1] Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain [2] Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: P A
authors.initials: PA
authors.lastname: Lazo
authors.affiliation: Department of Pathology, Centro Hospitalar São João/Medical Faculty and Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
authors.forename: F
authors.initials: F
authors.lastname: Carneiro
authors.affiliation: Department of Pathology, Centro Hospitalar São João/Medical Faculty and Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
authors.forename: C S
authors.initials: CS
authors.lastname: Moura
authors.affiliation: Department of Genetics, Portuguese Oncology Institute and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Vieira
authors.affiliation: Department of Genetics, Portuguese Oncology Institute and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
authors.forename: M R
authors.initials: MR
authors.lastname: Teixeira
authors.affiliation: 1] Cancer Epigenetics and Biology Progrm (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain [2] Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Spain [3] Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Esteller
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D005784:Gene Amplification; D018628:Gene Dosage; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011496:Protein Methyltransferases / Q000235:genetics* / Q000378:metabolism
chemical_list: D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human