Comment on Balestrieri et al. Sirtuin 6 Expression and Inflammatory Activity in Diabetic Atherosclerotic Plaques: Effects of Incretin Treatment. Diabetes 2015;64:1395–1406

Sirtuin 6 (SIRT6) is a NAD⁺-dependent deacetylase sirtuin family member that participates in multiple molecular pathways relating to genomic stability, metabolism, proliferation, differentiation, and apoptosis of cancer cells. However, the role of SIRT6 in health and disease is in considerable disagreement. Recently, Balestrieri et al. (1) indicated that lesser SIRT6 expression and more inflammation and oxidative stress were found in diabetic plaques, while plaques treated with drug therapies presented greater SIRT6 expression and less inflammation and oxidative stress. The results demonstrated that SIRT6 involved the inflammatory pathway(s) of diabetic atherosclerotic lesions. Zhang et al. (2) showed that SIRT6 was activated by p53 directly and interacted with forkhead box protein O1 (FoxO1), leading to FoxO1 deacetylation and nuclear exclusion. They suggested that SIRT6 might be relevant to tumor suppression. Furthermore, Sun et al. (3) manifested that SIRT6 played an important role in normal osteogenic differentiation, partly by repressing nuclear factor-κB signaling. In addition, Van Meter et al. (4) demonstrated that the suppression of SIRT6 on LINE1 retrotransposons was abolished, and these previously silenced retroelements were activated during the process of aging and in response to DNA damage.

These studies suggested that SIRT6 played a positive role in health and disease. However, Ming et al. (5) showed that skin-specific deletion of SIRT6 in mice inhibited skin tumorigenesis. The upregulation of SIRT6 expression was found in human skin squamous cell carcinoma. These results suggested that SIRT6 was an oncogene in the epidermis and played a complex role in epithelial carcinogenesis.

Together, these findings suggested that SIRT6 was not only implicated in the repression of the inflammation, oxidative stress, tumor, and aging, but also functioned as an oncogene in the epidermis. We read with interest the article by Balestrieri et al. (1) and thought that SIRT6 was a two-edged sword in health and disease.