Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha), a highly inducible transcriptional coactivator regulating energy homeostasis, is down-regulated in hepatoma tissues. To dissect its role in hepato-tumorigenesis, Ingenuity Pathway Analysis was applied to construct pathways affected by PGC-1alpha upregulation in HepG2 hepatoma cells based on our microarray data. Interestingly, migration of these cells was markedly diminished by PGC-1alpha overexpression in consistency with Ingenuity results. Moreover, a deduced expression increase of E-cadherin was also observed in PGC-1alpha-overexpressing HepG2 cells. Finally, transient transfection and chromatin-immunoprecipitation assays suggested that increased histone acetylation might be responsible for PGC-1alpha-mediated transactivation of a minimal E-cadherin promoter.