Abstract 5064: Sirt6 is a novel tumor suppressor in human urothelial cancer and activated by methysticin

Sirtuin 6 (SIRT6) plays an important role in longevity, metabolism, DNA-repair, and inflammatory response. In human urothelial cancer, a high level of SIRT6 expression predicts a better survival for patients. We found that overexpression of SIRT6 in human muscle-invasive bladder cancer cell line J82 reduced cell migration and invasion, but didn’t reduce the in vitro cell growth. Kava is a traditional psychotropic beverage made from the rhizomes of Piper methysticum G. Forst. Previous epidemiological studies have shown an inverse relationship between cancer incidence and kava consumption in South Pacific Island Nations. We have shown that Methysticin, a major kavalactone in the Kava plant, inhibits the growth, migration and invasion of bladder cancer lines. However, these anti-cancer activities of Methysticin are attenuated in cells with low expression of SIRT6, expression of enzymatically mutant SIRT6 or SIRT6 knockout, which suggested that the anti-cancer activities of Methysticin are at least in part dependent on SIRT6 expression. Molecular modelling indicates that Methysticin docks into the site next to a loop near the acetylated peptide substrate binding site of SIRT6. The Cellular Thermal Shift Assay (CETSA, an in vivo assay) demonstrated that Methysticin significantly decreased heat-induced protein degradation of SIRT6. Treatment of J82 cells with Methysticin also resulted in a dose-dependent reduction of H3K18 acetylation. Taken together, these results suggest that Methysticin acts a novel SIRT6 activator for its anti-bladder activity. Further studies have demonstrated that Methysticin activates the TBK1/IRF3/STING pathway by increasing the protein expression of TBK1 and the phosphorylation of TBK1 and STING, which suggest that Methysticin may be able to enhance anti-tumor immunity. Therefore, our results support further investigation of Methylation for bladder cancer prevention. Note: This abstract was not presented at the meeting. Citation Format: DongJun Fu, Noriko N. Yokoyama, Mattew Tippin, Xiaolin Zi. Sirt6 is a novel tumor suppressor in human urothelial cancer and activated by methysticin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5064.