AMP-activated Protein Kinase Regulates β-Catenin Transcription via Histone Deacetylase 5

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism; it is inhibited under obese conditions and is activated by exercise and by many anti-diabetic drugs. Emerging evidence also suggests that AMPK regulates cell differentiation, but the underlying mechanisms are unclear. We hypothesized that AMPK regulates cell differentiation via altering beta-catenin expression, which involves phosphorylation of class IIa histone deacetylase 5 (HDAC5). In both C3H10T1/2 cells and mouse embryonic fibroblasts (MEFs), AMPK activity was positively correlated with beta-catenin content. Chemical inhibition of HDAC5 increased beta-catenin mRNA expression. HDAC5 overexpression reduced and HDAC5 knockdown increased H3K9 acetylation and cellular beta-catenin content. HDAC5 formed a complex with myocyte enhancer factor-2 to down-regulate beta-catenin mRNA expression. AMPK phosphorylated HDAC5, which promoted HDAC5 exportation from the nucleus; mutation of two phosphorylation sites in HDAC5, Ser-259 and -498, abolished the regulatory role of AMPK on beta-catenin expression. In conclusion, AMPK promotes beta-catenin expression through phosphorylation of HDAC5, which reduces HDAC5 interaction with the beta-catenin promoter via myocyte enhancer factor-2. Thus, the data indicate that AMPK regulates cell differentiation and development via cross-talk with the wingless and Int (Wnt)/beta-catenin signaling pathway.