Fig. 7

Model of HNF4α isoform and BMAL1 expression in normal vs. cancer cells. In normal hepatocytes, the P1-HNF4α isoform and the circadian protein BMAL1 are concomitantly expressed. While BMAL1 is found in both nuclear and cytoplasmic compartments, P1-HNF4α is found exclusively in the nucleus, where it both activates and represses target genes, sometimes in a circadian manner. In HCC, P2-HNF4α is induced, resulting in either the dual expression of both P1-HNF4α and P2-HNF4α or only P2-HNF4α in HNF4α-positive tumors (approximately 50% of HCC). Induction of P2-HNF4α results in direct transcriptional repression of BMAL1 and a large portion of P1-HNF4α becomes cytoplasmic, reducing its ability to repress target cyclin and EMT genes in a circadian manner. Forced expression of BMAL1 in HNF4α-positive HCC results in a cell death and inhibition of tumor growth