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

Chi-Wai Lee, Leo Lap-Yan Wong, Edith Yuk-Ting Tse, Heong-Fai Liu, Veronica Yee-Law Leong, Joyce Man-Fong Lee, D.Grahame Hardie, Irene Oi-Ling Ng, Yick-Pang Ching

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    126 Citations (Scopus)

    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 a2 catalytic subunit isoform of AMPK is significantly downregulated in hepatocellular carcinoma (HCC). Clinicopathologic analysis revealed that underexpression of AMPK-a2 was statistically associated with an undifferentiated cellular phenotype and poor patient prognosis. Loss of AMPK-a2 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.
    Original languageEnglish
    Pages (from-to)4394-4404
    Number of pages11
    JournalCancer Research
    Volume72
    Issue number17
    DOIs
    Publication statusPublished - 2012

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    Lee, C-W., Wong, L. L-Y., Tse, E. Y-T., Liu, H-F., Leong, V. Y-L., Lee, J. M-F., Hardie, D. G., Ng, I. O-L., & Ching, Y-P. (2012). AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells. Cancer Research, 72(17), 4394-4404. https://doi.org/10.1158/0008-5472.CAN-12-0429