Hepatic Circadian and Differentiation Factors Control Liver Susceptibility for Fatty Liver Disease and Tumorigenesis

Authors

Baharan Fekry
Aleix Ribas-Latre
Rachel Van Drunen
Rafael Bravo Santos
Samay Shivshankar
Yulin Dai
Zhongming Zhao
Seung-Hee Yoo
Zheng Chen
Kai Sun
Frances M Sladek
Mamoun Younes
Kristin Eckel-Mahan

Publication Date

9-1-2022

Journal

The FASEB Journal

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.

Keywords

ARNTL Transcription Factors, Animals, Carcinogenesis, Carcinoma, Hepatocellular, Cell Transformation, Neoplastic, Liver, Liver Neoplasms, Mice