AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells
Menée in vitro et in vivo, cette étude montre que, en déstabilisant le gène p53 par l'intermédiaire de la déacétylase ZIRT1, une sous-expression de la kinase AMPK favorise la formation d'un carcinome hépatocellulaire
AMP-activated protein kinase (AMPK), a biological 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 down-regulated in hepatocellular carcinoma (HCC). Clinicopathological analysis revealed that under-expression of AMPK-α2 was statistically associated with an undifferentiated cellular phenotype and poor patient prognosis. Loss of AMPK-α2 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 Thr-344, promoting p53 acetylation and apoptosis of HCC cells. Taken together, our findings suggest that under-expression of AMPK is frequently observed in HCC, and that inactivation of AMPK promotes hepatocarcinogenesis by destabilizing p53 in a SIRT1-dependent manner.