Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion

Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10684-9. doi: 10.1073/pnas.1411026111.

Ping Zhang ¹, Bo Tu ¹, Hua Wang ², Ziyang Cao ¹, Ming Tang ¹, Chaohua Zhang ¹, Bo Gu ¹, Zhiming Li ¹, Lina Wang ¹, Yang Yang ¹, Ying Zhao ¹, Haiying Wang ¹, Jianyuan Luo ¹, Chu-Xia Deng ³, Bin Gao ², Robert G Roeder ⁴, Wei-Guo Zhu ⁵

Affiliations

1 Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
2 Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892;
3 Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;
4 Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065; and zhuweiguo@bjmu.edu.cn roeder@rockefeller.edu.
5 Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;Center for Life Sciences, Peking-Tsinghua University, Beijing 100871, China zhuweiguo@bjmu.edu.cn roeder@rockefeller.edu.

PMID: 25009184 DOI: 10.1073/pnas.1411026111

Abstract

In mammalian cells, tumor suppressor p53 plays critical roles in the regulation of glucose metabolism, including glycolysis and Oxidative Phosphorylation, but whether and how p53 also regulates gluconeogenesis is less clear. Here, we report that p53 efficiently down-regulates the expression of phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC), which encode rate-limiting Enzymes in gluconeogenesis. Cell-based assays demonstrate the p53-dependent nuclear exclusion of forkhead box protein O1 (FoxO1), a key transcription factor that mediates activation of PCK1 and G6PC, with consequent alleviation of FoxO1-dependent gluconeogenesis. Further mechanistic studies show that p53 directly activates expression of the NAD(+)-dependent histone deacetylase Sirtuin 6 (SIRT6), whose interaction with FoxO1 leads to FoxO1 deacetylation and export to the cytoplasm. In support of these observations, p53-mediated FoxO1 nuclear exclusion, down-regulation of PCK1 and G6PC expression, and regulation of glucose levels were confirmed in C57BL/J6 mice and in liver-specific SIRT6 conditional knockout mice. Our results provide insights into mechanisms of metabolism-related p53 functions that may be relevant to tumor suppression.

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