Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis

Baharan Fekry, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
Aleix Ribas-Latre, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
Rachel Van Drunen, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
Rafael Bravo Santos, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
Samay Shivshankar, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
Yulin Dai, Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, Texas, USA.
Zhongming Zhao, Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, Texas, USA.
Seung-Hee Yoo, Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
Zheng Chen, Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
Kai Sun, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.
Frances M. Sladek, Department of Molecular, Cell and Systems Biology, University of California, Riverside, California, USA.
Mamoun Younes, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
Kristin Eckel-Mahan, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.

Document Type

Journal Article

Publication Date

9-1-2022

Journal

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Volume

36

Issue

9

DOI

10.1096/fj.202101398R

Keywords

BMAL1; HCC; HNF4α; SR9009; circadian; hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α- either by isoform switching, or loss of expression- results in an increased risk for HCC, while BMAL1 gain-of-function in HNF4α-positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen-induced liver injury and in the "STAM" model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α-deficient, BMAL1-positive HCC with REV-ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV-ERB-dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics.

Department

Pathology

Link to Full Text

Share

COinS