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

Sivan Elhanati, Rotem Ben-Hamo, Yariv Kanfi, Alexander Varvak, Renana Glazz, Batia Lerrer, Sol Efroni, Haim Y. Cohen

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

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. 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.

Original languageEnglish
Pages (from-to)234-242
Number of pages9
JournalCell Reports
Volume14
Issue number2
DOIs
StatePublished - 12 Jan 2016

Bibliographical note

Funding Information:
We thank Shoshana Naiman and the members of the Cohen lab for their helpful comments on the manuscript. This study was supported by the Israel Science Foundation, I-Core Foundation, Israeli Ministry of Health, TEVA NNE program, ESFD, and the ERC: European Research Council.

Publisher Copyright:
© 2016 The Authors.

Keywords

  • Fatty acid oxidation
  • SIRT6
  • miR-122

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