In the present study, we demonstrated the following: (1) in hepatocyte derived cells, overexpression of the TCF-4J isoform lacking the SxxSS motif, exhibited robust tumorigenic potential; (2) the TCF-4J isoform was highly expressed in rapidly growing and presumably in the hypoxic milieu of human PD HCC, and (3) TCF-4J expression contributed to nuclear accumulation of HIF-2α and was due to, in part, less ubiquitin-dependent degradation of HIF-αs in J cells compared to K cells under severe hypoxia. The gene discussed is EPAS1; the disease is hepatocellular carcinoma.