Reciprocal Regulation between SIRT6 and miR-122 Controls Liver Metabolism and Predicts Hepatocarcinoma Prognosis

Mice overexpressing the longevity protein SIRT6 or deficient for the liver’s most prevalent microRNA miR-122 display a similar set of phenotypes, including improved lipid profile and protection against damage linked to obesity. Here, we show that miR-122 and SIRT6 negatively regulate each other’s expression. SIRT6 downregulates miR-122 by deacetylating H3K56 in the promoter region. MiR-122 binds to three sites on the SIRT6 3′ UTR and reduces its levels. The interplay between SIRT6 and miR-122 is manifested in two physiologically relevant ways in the liver. First, they oppositely regulate a similar set of metabolic genes and fatty acid β-oxidation. Second, in hepatocellular carcinoma patients, loss of a negative correlation between SIRT6 and miR-122 expression is significantly associated with better prognosis. These findings show that SIRT6 and miR-122 negatively regulate each other to control various aspects of liver physiology and SIRT6-miR-122 correlation may serve as a biomarker for hepatocarcinoma prognosis. [Display omitted] •SIRT6 and miR-122 negatively regulate each other•MiR-122 differentially represses SIRT6 depending on its 3′ UTR binding site number•SIRT6 and miR-122 co-regulate fatty acid beta oxidation•Loss of this SIRT6-miR-122 relationship correlates with HCC prognosis Elhanati et al. find that SIRT6 and miR-122 negatively regulate each other. The interplay between them is linked to regulation of a shared set of metabolic genes and fatty acid β-oxidation and may present a biomarker for hepatocarcinoma prognosis.