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We recently reported an atypical epithelial mesenchymal transition (EMT) in human hepatoma cell culture Huh7.5, which was non-responsive to the canonical EMT-transcription factors. Here we characterize major pathways regulating this atypical EMT through whole genome transcriptome profiling and molecular analysis, and identify a unique regulation of EMT by GSK-3β. Our analysis reveals remarkable suppression of several key liver-specific markers in Huh7.5M cells indicating that EMT not only changes the epithelial properties, but alters the characteristics associated with hepatocytes as well. One key finding of this study is that GSK-3β, a known antagonist to β-Catenin signaling and a major pro-apoptotic regulator, is critical for the maintenance of EMT in Huh7.5M cells as its inhibition reversed EMT. Importantly, through these studies we identify that maintenance of EMT by GSK-3β in Huh7.5M is regulated by …