CEFYBO   02669
CENTRO DE ESTUDIOS FARMACOLOGICOS Y BOTANICOS
Unidad Ejecutora - UE
artículos
Título:
Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer
Autor/es:
SITA KUGEL; JESSICA L. FELDMAN; MARK A. KLEIN,4; DAFNE M SILBERMAN; CARLOS SEBASTIÁN; CRAIG MERMEL; STEPHANIE DOBERSCH; ABBE R. CLARK; GAD GETZ; JOHN M. DENU; RAUL MOSTOSLAVSKY
Revista:
Cell Reports
Editorial:
Elsevier
Referencias:
Año: 2015 vol. 13 p. 1 - 10
ISSN:
2211-1247
Resumen:
Chromatin factors have emerged as the mostfrequently dysregulated family of proteins in cancer.We have previously identified the histone deacety-lase SIRT6 as a key tumor suppressor, yet whetherpoint mutations are selected for in cancer remainsunclear. In this manuscript, we characterized natu-rally occurring patient-derived SIRT6 mutations.Strikingly, all the mutations significantly affectedeither stability or catalytic activity of SIRT6, indi-cating that these mutations were selected for inthese tumors. Further, the mutant proteins failed torescue sirt6 knockout (SIRT6 KO) cells, as measuredby the levels of histone acetylation at glycolyticgenes and their inability to rescue the tumorigenicpotential of these cells. Notably, the main activityaffected in the mutants was histone deacetylationrather than demyristoylation, pointing to the formeras the main tumor-suppressive function for SIRT6.Our results identified cancer-associated point muta-tions in SIRT6, cementing its function as a tumor sup-pressor in human cancer.