Tier 3 — preclinical

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

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
Cell Reports 2015 13(3):479-488

Bibliography

PubMed
PMID 26456828
DOI
10.1016/j.celrep.2015.09.022
Funding
Supported by NIH grants including R01 CA175727, R21 CA198109, R01 GM093072, R01 GM065386, DK088190 and Canadian Institutes of Health Research support.

Study snapshot

DesignCancer-genomics identification of patient-derived mutations plus biochemical and cell-function experiments.
ModelHuman cancer-associated SIRT6 variants and SIRT6-knockout/rescue cellular models.
SampleMultiple patient-derived variants and mechanistic cellular assays.
InterventionExpression and functional testing of cancer-associated SIRT6 point mutations.
DurationExperimental.
EndpointsSIRT6 protein stability; Histone deacetylase activity; Glycolytic gene acetylation; Tumorigenic potential

What the study showed, in plain terms

Naturally occurring SIRT6 mutations found in human tumors impaired SIRT6 stability or catalytic activity and failed to restore normal tumor-suppressive functions in SIRT6-deficient cells.

Key findings

The cancer-associated mutations mainly disrupted SIRT6 histone deacetylation and supported the view that loss of SIRT6 function can be selected for in some human cancers.

What this study can and cannot tell us

The study supports a tumor-suppressive role in selected cancers but does not mean SIRT6 is uniformly tumor-suppressive across all cancer types.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability