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.

Details

Title
Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma
Author
Baharan Fekry 1 ; Ribas-Latre, Aleix 1 ; Baumgartner, Corrine 1 ; Deans, Jonathan R 2 ; Kwok, Christopher 1 ; Patel, Pooja 3 ; Fu, Loning 3 ; Berdeaux, Rebecca 4 ; Sun, Kai 5 ; Kolonin, Mikhail G 1   VIAFID ORCID Logo  ; Wang, Sidney H 1 ; Yoo, Seung-Hee 6 ; Sladek, Frances M 2 ; Eckel-Mahan, Kristin 5   VIAFID ORCID Logo 

1  Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, USA 
2  Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, CA, USA 
3  Department of Pediatrics, Molecular and Cellular Biology, Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA 
4  Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, USA; Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, USA 
5  Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, USA; Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, USA 
6  Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, USA 
Pages
1-17
Publication year
2018
Publication date
Oct 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-06648-6
ProQuest document ID
2123043057
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.