Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma.

Abstract

Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of liver-specific gene expression with potent tumor suppressor activity, yet many liver tumors express HNF4α. This study reveals that P1-HNF4α, the predominant isoform expressed in the adult liver, inhibits expression of tumor promoting genes in a circadian manner. In contrast, an additional isoform of HNF4α, driven by an alternative promoter (P2-HNF4α), is induced in HNF4α-positive human hepatocellular carcinoma (HCC). P2-HNF4α represses the circadian clock gene ARNTL (BMAL1), which is robustly expressed in healthy hepatocytes, and causes nuclear to cytoplasmic re-localization of P1-HNF4α. We reveal mechanisms underlying the incompatibility of BMAL1 and P2-HNF4α in HCC, and demonstrate that forced expression of BMAL1 in HNF4α-positive HCC prevents the growth of tumors in vivo. These data suggest that manipulation of the circadian clock in HNF4α-positive HCC could be a tractable strategy to inhibit tumor growth and progression in the liver.

• Authors: Baharan Fekry, Aleix Ribas-Latre, Corrine Baumgartner, Jonathan R Deans, Christopher Kwok, Pooja Patel, Loning Fu, Rebecca Berdeaux, Kai Sun, Mikhail G Kolonin, Sidney H Wang, Seung-Hee Yoo, Frances M Sladek, Kristin Eckel-Mahan
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 4349 (10 19 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 30341289 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ARNTL Transcription Factors
• ARNTL protein, human
• HNF4A protein, human
• Hepatocyte Nuclear Factor 4
• Protein Isoforms

Topics

• ARNTL Transcription Factors (genetics, metabolism)
• Active Transport, Cell Nucleus
• Carcinoma, Hepatocellular (metabolism, pathology)
• Circadian Clocks
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Hepatocyte Nuclear Factor 4 (genetics, metabolism, physiology)
• Hepatocytes (metabolism)
• Liver Neoplasms (metabolism, pathology)
• Protein Isoforms (physiology)