Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer

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 natural...

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Main Authors:	Sita Kugel, Jessica L. Feldman, Mark A. Klein, Dafne M. Silberman, Carlos Sebastián, Craig Mermel, Stephanie Dobersch, Abbe R. Clark, Gad Getz, John M. Denu, Raul Mostoslavsky
Format:	Article
Language:	English
Published:	Elsevier 2015-10-01
Series:	Cell Reports
Online Access:	http://www.sciencedirect.com/science/article/pii/S2211124715010335

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spelling	doaj-87ae949b80cd4ccfad5866d617c43fc62020-11-24T21:21:54ZengElsevierCell Reports2211-12472015-10-0113347948810.1016/j.celrep.2015.09.022Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in CancerSita Kugel0Jessica L. Feldman1Mark A. Klein2Dafne M. Silberman3Carlos Sebastián4Craig Mermel5Stephanie Dobersch6Abbe R. Clark7Gad Getz8John M. Denu9Raul Mostoslavsky10The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USAThe Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USAThe Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USACenter for Pharmacological and Botanical Studies (CEFYBO)-CONICET, Facultad de Medicina, UBA, Buenos Aires 1121, ArgentinaThe Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USAThe Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USAMax-Planck-Institute for Heart and Lung Research, Bad Nauheim 61231, GermanyThe Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USAThe Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USAThe Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USAThe Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USAChromatin 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.http://www.sciencedirect.com/science/article/pii/S2211124715010335
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Sita Kugel Jessica L. Feldman Mark A. Klein Dafne M. Silberman Carlos Sebastián Craig Mermel Stephanie Dobersch Abbe R. Clark Gad Getz John M. Denu Raul Mostoslavsky
spellingShingle	Sita Kugel Jessica L. Feldman Mark A. Klein Dafne M. Silberman Carlos Sebastián Craig Mermel Stephanie Dobersch Abbe R. Clark Gad Getz John M. Denu Raul Mostoslavsky Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer Cell Reports
author_facet	Sita Kugel Jessica L. Feldman Mark A. Klein Dafne M. Silberman Carlos Sebastián Craig Mermel Stephanie Dobersch Abbe R. Clark Gad Getz John M. Denu Raul Mostoslavsky
author_sort	Sita Kugel
title	Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer
title_short	Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer
title_full	Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer
title_fullStr	Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer
title_full_unstemmed	Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer
title_sort	identification of and molecular basis for sirt6 loss-of-function point mutations in cancer
publisher	Elsevier
series	Cell Reports
issn	2211-1247
publishDate	2015-10-01
description	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.
url	http://www.sciencedirect.com/science/article/pii/S2211124715010335
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Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer

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