Reciprocal Regulation between SIRT6 and miR-122 Controls Liver Metabolism and Predicts Hepatocarcinoma Prognosis
Reciprocal Regulation between SIRT6 and miR-122 Controls Liver Metabolism and Predicts Hepatocarcinoma Prognosis
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DOI：
10.1016/j.celrep.2015.12.023
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发表时间：
2016-01-12
期刊：
影响因子：
8.8
通讯作者：
Cohen, Haim Y.
中科院分区：
文献类型：
--
作者：
Elhanati, Sivan;Ben-Hamo, Rotem;Cohen, Haim Y.
过表达长寿蛋白SIRT 6或缺乏肝脏最普遍的microRNA miR-122的小鼠显示出类似的表型，包括改善的脂质谱和保护免受与肥胖相关的损伤。在这里，我们发现miR-122和SIRT 6负调控彼此的表达。SIRT 6通过使启动子区中的H3 K56脱乙酰化来下调miR-122。miR-122结合SIRT 6 3' UTR上的三个位点并降低其水平。SIRT 6和miR-122之间的相互作用在肝脏中以两种生理相关的方式表现出来。首先，它们反向调节一组类似的代谢基因和脂肪酸β-氧化。其次，在肝细胞癌患者中，SIRT 6和miR-122表达之间负相关性的丧失与更好的预后显著相关。这些发现表明，SIRT 6和miR-122相互负调节以控制肝脏生理学的各个方面，SIRT 6-miR-122相关性可作为肝癌预后的生物标志物。
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 beta-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.