title: Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer.
abstract: Chromatin factors have emerged as the most frequently dysregulated family of proteins in cancer. We have previously identified the histone deacetylase SIRT6 as a key tumor suppressor, yet whether point mutations are selected for in cancer remains unclear. In this manuscript, we characterized naturally occurring patient-derived SIRT6 mutations. Strikingly, all the mutations significantly affected either stability or catalytic activity of SIRT6, indicating that these mutations were selected for in these tumors. Further, the mutant proteins failed to rescue sirt6 knockout (SIRT6 KO) cells, as measured by the levels of histone acetylation at glycolytic genes and their inability to rescue the tumorigenic potential of these cells. Notably, the main activity affected in the mutants was histone deacetylation rather than demyristoylation, pointing to the former as the main tumor-suppressive function for SIRT6. Our results identified cancer-associated point mutations in SIRT6, cementing its function as a tumor suppressor in human cancer.
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sita
authors.initials: S
authors.lastname: Kugel
authors.affiliation: The Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Feldman
authors.affiliation: The Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Klein
authors.affiliation: Center for Pharmacological and Botanical Studies (CEFYBO)-CONICET, Facultad de Medicina, UBA, Buenos Aires 1121, Argentina.
authors.forename: Dafne M
authors.initials: DM
authors.lastname: Silberman
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sebastián
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Mermel
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dobersch
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Abbe R
authors.initials: AR
authors.lastname: Clark
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: The Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA. Electronic address: jmdenu@wisc.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Denu
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The Center for Regenerative Medicine, The Massachusetts General Hospital, Boston, MA 02114, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: rmostoslavsky@mgh.harvard.edu.
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics*; D017354:Point Mutation; D037761:Sirtuins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C516592:SIRT6 protein, human; D037761:Sirtuins