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

Area of Science:

• Molecular Biology
• Oncology
• Biochemistry

Background:

• Chromatin factors are frequently altered in cancer.
• SIRT6, a histone deacetylase, is a known tumor suppressor.
• The role of specific SIRT6 point mutations in cancer has not been fully elucidated.

Purpose of the Study:

• To investigate naturally occurring patient-derived mutations in SIRT6.
• To determine the impact of these mutations on SIRT6 stability, catalytic activity, and tumor-suppressive functions.

Main Methods:

• Characterization of patient-derived SIRT6 mutations.
• Assessment of mutant SIRT6 protein stability and catalytic activity.
• Evaluation of SIRT6 mutant function in sirt6 knockout (SIRT6 KO) cells, including histone acetylation levels and tumorigenic potential.

Main Results:

• All characterized patient-derived SIRT6 mutations significantly affected protein stability or catalytic activity.
• Mutant SIRT6 proteins failed to rescue SIRT6 KO cells, evidenced by increased histone acetylation at glycolytic genes.
• Mutations primarily impacted histone deacetylation, not demyristoylation, suggesting histone deacetylation is key to SIRT6's tumor suppression.

Conclusions:

• Cancer-associated point mutations in SIRT6 have been identified.
• These mutations disrupt SIRT6's tumor-suppressive functions, confirming its role in human cancer.
• Histone deacetylation is identified as the primary tumor-suppressive mechanism of SIRT6.