The transcriptional activity of Gli1 is negatively regulated by AMPK through Hedgehog partial agonism in hepatocellular carcinoma

The aberrant activation of the Hedgehog (Hh) signaling pathway has been implicated in a variety of malignancies, including hepatocellular carcinoma (HCC). The mammalian 5′ adenosine monophosphate-activated protein kinase (AMPK) plays a crucial role in cellular energy homeostasis. However, the interaction between the Hh and AMPK signaling pathways has not been investigated to date. In the present study, to the best of our knowlege, we report for the first time the negative regulation of glioma-associated oncogene 1 (Gli1), an important downstream effector of Hh, by the AMPK signal transduction pathway. Immunoprecipitation and GST-pull down assay showed a direct interaction between AMPK and Gli1. The overexpression of AMPK induced the downregulation of Gli1 expression, while the knockdown of AMPK upregulated Gli1 expression in a relatively short period of time (24 h or less). Our data suggest that AMPK may function as an upstream molecule that regulates Gli1 expression. Therefore, AMPK may play a role in the Hh signaling pathway, through which it regulates tumorigenesis.