title: Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells.
abstract: Multiple myeloma (MM) is characterized by a highly unstable genome, with aneuploidy observed in nearly all patients. The mechanism causing this karyotypic instability is largely unknown, but recent observations have correlated these abnormalities with dysfunctional DNA damage response. Here, we show that the NAD(+)-dependent deacetylase SIRT6 is highly expressed in MM cells, as an adaptive response to genomic stability, and that high SIRT6 levels are associated with adverse prognosis. Mechanistically, SIRT6 interacts with the transcription factor ELK1 and with the ERK signaling-related gene. By binding to their promoters and deacetylating H3K9 at these sites, SIRT6 downregulates the expression of mitogen-activated protein kinase (MAPK) pathway genes, MAPK signaling, and proliferation. In addition, inactivation of ERK2/p90RSK signaling triggered by high SIRT6 levels increases DNA repair via Chk1 and confers resistance to DNA damage. Using genetic and biochemical studies in vitro and in human MM xenograft models, we show that SIRT6 depletion both enhances proliferation and confers sensitization to DNA-damaging agents. Our findings therefore provide insights into the functional interplay between SIRT6 and DNA repair mechanisms, with implications for both tumorigenesis and the treatment of MM.
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Clinic of Hematology, Department of Internal Medicine, University of Genoa, Istituto di Ricovero e Cura a Carattere Scientifico Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Genoa, Italy;
authors.forename: Michele
authors.identifier: http://orcid.org/0000-0002-1530-6729
authors.initials: M
authors.lastname: Cea
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Clinic of Hematology, Department of Internal Medicine, University of Genoa, Istituto di Ricovero e Cura a Carattere Scientifico Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Genoa, Italy;
authors.forename: Antonia
authors.identifier: http://orcid.org/0000-0003-1973-3768
authors.initials: A
authors.lastname: Cagnetta
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Sophia
authors.initials: S
authors.lastname: Adamia
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Chirag
authors.initials: C
authors.lastname: Acharya
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ohguchi
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Aditya
authors.initials: A
authors.lastname: Munshi
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Prakrati
authors.initials: P
authors.lastname: Acharya
authors.affiliation: Beth Israel Deaconess Medical Center Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA; and.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Bhasin
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Ruben
authors.initials: R
authors.lastname: Carrasco
authors.affiliation: Clinic of Hematology, Department of Internal Medicine, University of Genoa, Istituto di Ricovero e Cura a Carattere Scientifico Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Genoa, Italy;
authors.forename: Fiammetta
authors.initials: F
authors.lastname: Monacelli
authors.affiliation: Clinic of Hematology, Department of Internal Medicine, University of Genoa, Istituto di Ricovero e Cura a Carattere Scientifico Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Genoa, Italy;
authors.forename: Alberto
authors.initials: A
authors.lastname: Ballestrero
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.affiliation: Clinic of Hematology, Department of Internal Medicine, University of Genoa, Istituto di Ricovero e Cura a Carattere Scientifico Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Genoa, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.affiliation: Clinic of Hematology, Department of Internal Medicine, University of Genoa, Istituto di Ricovero e Cura a Carattere Scientifico Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Genoa, Italy;
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Lemoli
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.affiliation: Clinic of Hematology, Department of Internal Medicine, University of Genoa, Istituto di Ricovero e Cura a Carattere Scientifico Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Genoa, Italy;
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D004260:DNA Repair; D004317:Doxorubicin / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology*; D009153:Mutagens / Q000633:toxicity; D011379:Prognosis; D037761:Sirtuins / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: C494112:ELK1 protein, human; D006657:Histones; D009153:Mutagens; D050807:ets-Domain Protein Elk-1; D004317:Doxorubicin; C516592:SIRT6 protein, human; D037761:Sirtuins; D008239:Lysine