Fig. 1.

Dual roles for SIRT6 in cancer. SIRT6 has been reported to have both tumor suppressor and oncogenic properties. Reduced levels of SIRT6 have been described in colon cancer (CC), hepatocellular carcinoma (HCC), pancreatic cancer (PaC) and head and neck squamous cell carcinoma (HNSCC), correlating with increased cancer stage and grade, and/or with a shortened time to relapse in comparison to tumors with higher levels of SIRT6. SIRT6 can protect against tumorigenesis through multiple pathways: (1) inhibition of HIF-1α and MYC transcriptional activity, which decreases glycolysis and cellular proliferation, respectively; (2) inhibition of the anti-apoptotic factor survivin; (3) activation of the p53 and p73 apoptosis pathways in cancer cells specifically. Furthermore, SIRT6 represses SREBP1 and SREBP2 (SREBP1/2) and JUN activity, resulting in reduced lipogenesis and insulin–IGF-1-like signaling (IIS), respectively. Both of these processes likely impact cancer cell proliferation. By contrast, high SIRT6 levels have been reported in breast cancer (BC), PaC and prostate cancer (PrC), and are associated with drug resistance and poor prognosis. High SIRT6 levels promote cellular proliferation through deacetylation of the cell cycle control proteins FOXO3a and p53, and increase IL-8- and TNF-mediated inflammatory responses, angiogenesis and tumor metastasis in part through activation of the Ca²⁺ channel TRPM2. Ac, acetyl group; TNF, tumor necrosis factor; IL-8, interleukin-8.