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AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells.


ABSTRACT: AMP-activated protein kinase (AMPK), a biologic sensor for cellular energy status, has been shown to act upstream and downstream of known tumor suppressors. However, whether AMPK itself plays a tumor suppressor role in cancer remains unclear. Here, we found that the ?2 catalytic subunit isoform of AMPK is significantly downregulated in hepatocellular carcinoma (HCC). Clinicopathologic analysis revealed that underexpression of AMPK-?2 was statistically associated with an undifferentiated cellular phenotype and poor patient prognosis. Loss of AMPK-?2 in HCC cells rendered them more tumorigenic than control cells both in vitro and in vivo. Mechanistically, ectopic expression of AMPK enhanced the acetylation and stability of p53 in HCC cells. The p53 deacetylase, SIRT1, was phosphorylated and inactivated by AMPK at Thr344, promoting p53 acetylation and apoptosis of HCC cells. Taken together, our findings suggest that underexpression of AMPK is frequently observed in HCC, and that inactivation of AMPK promotes hepatocarcinogenesis by destabilizing p53 in a SIRT1-dependent manner.

SUBMITTER: Lee CW 

PROVIDER: S-EPMC3433393 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells.

Lee Chi-Wai CW   Wong Leo Lap-Yan LL   Tse Edith Yuk-Ting EY   Liu Heong-Fai HF   Leong Veronica Yee-Law VY   Lee Joyce Man-Fong JM   Hardie D Grahame DG   Ng Irene Oi-Lin IO   Ching Yick-Pang YP  

Cancer research 20120622 17


AMP-activated protein kinase (AMPK), a biologic sensor for cellular energy status, has been shown to act upstream and downstream of known tumor suppressors. However, whether AMPK itself plays a tumor suppressor role in cancer remains unclear. Here, we found that the α2 catalytic subunit isoform of AMPK is significantly downregulated in hepatocellular carcinoma (HCC). Clinicopathologic analysis revealed that underexpression of AMPK-α2 was statistically associated with an undifferentiated cellular  ...[more]

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