AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells.
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 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 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.
Departments of Anatomy and Pathology, Li Ka Shing Faculty of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
Chi-Wai
CW
Lee
Leo Lap-Yan
LL
Wong
Edith Yuk-Ting
EY
Tse
Heong-Fai
HF
Liu
Veronica Yee-Law
VY
Leong
Joyce Man-Fong
JM
Lee
D Grahame
DG
Hardie
Irene Oi-Lin
IO
Ng
Yick-Pang
YP
Ching
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1