Finnish Study Describes Activators of SIRT6 Gene

A team of Finnish researchers conducted a study to evaluate the differences in chemical features between inhibitors and activators of the cancer-related SIRT6 gene.

SIRT6 (Sirtuin 6) is a chromatin-associated enzyme that is required for normal base excision repair of DNA damage in mammalian cells. Deficiency of SIRT6 in mice leads to abnormalities that overlap with aging-associated degenerative processes. SIRT6 also promotes the repair of DNA double-strand breaks by the process of non-homologous end joining.

Flavonoids are polyphenolic secondary metabolites synthesized by plants and fungi with various pharmacological effects. Due to their many classes of biological activity, they have been studied extensively in drug development. Flavonoids have been shown to modulate the activity of a NAD+-dependent histone deacetylase, SIRT6. Since SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction, it is an interesting target in inflammatory and metabolic diseases as well as in cancer.

Investigators at the University of Eastern Finland (Kuopio, Finland) reported in the March 7, 2018, online edition of the journal Scientific Reports that flavonoids could alter SIRT6 activity in a structure dependent manner. Catechin derivatives with galloyl moiety displayed significant inhibition potency against SIRT6 at 10 microMolar concentration. The most potent SIRT6 activator, cyanidin, belonged to the family of anthocyanidins, and produced a 55-fold increase in SIRT6 activity compared to the three to 10-fold increase for the others. Cyanidin was also found to significantly increase SIRT6 expression in human colon adenocarcinoma Caco-2 cells. Cyanidin also decreased the expression of the TWIST1 and GLUT1 cancer promoter genes in Caco-2 cells, while increasing the expression of the tumor suppressor FOXO3 gene in the cells.

Results from docking studies indicated possible binding sites for SIRT6 inhibitors and activators. Inhibitors likely attached in a manner that could disturb NAD+ binding. The putative activator-binding site was found next to a loop near the acetylated peptide substrate-binding site. In some cases, the activators changed the conformation of this loop suggesting that it might play a role in SIRT6 activation.

"The most interesting results of our study relate to cyanidin, which is an anthocyanin found abundantly in wild bilberry, blackcurrant, and lingonberry," said first author Dr. Minna Rahnasto-Rilla, pharmacology researcher at the University of Eastern Finland.

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University of Eastern Finland