Details

Autor(en) / Beteiligte

• Kugel, Sita
• Feldman, Jessica L.
• Klein, Mark A.
• Silberman, Dafne M.
• Sebastián, Carlos
• Mermel, Craig
• Dobersch, Stephanie
• Clark, Abbe R.
• Getz, Gad
• Denu, John M.
• Mostoslavsky, Raul

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2015-10, Vol.13 (3), p.479-488

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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. [Display omitted] •Eight loss-of-function SIRT6 mutations were identified in human cancers•SIRT6 mutants alter either SIRT6 stability, localization, or enzymatic activity•SIRT6 mutants fail to repress glycolysis and cellular transformation•Deacetylase, not demyristoylase, activity is critical for SIRT6 tumor-suppressor function Kugel et al. identified eight naturally occurring tumor-associated point mutations in SIRT6 that alter stability, localization, or enzymatic activity. Based on biochemical, biological, and structural analyses, these mutations render SIRT6 unable to repress transformation. These mutations demonstrate that SIRT6 deacetylase activity, not demyristoylase activity, is critical for SIRT6 tumor-suppressor functions.