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Title: Incompatibility of the circadian protein BMAL1 and HNF 4a in hepatocellular carcinoma

Author
item FEKRY, BAHARAN - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item RIBAS-LATRE, ALEIX - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item BAUMGARTNER, CORRINE - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item DEANS, JONATHAN - UNIVERSITY OF CALIFORNIA
item KWOK, CHRISTOPHER - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item PATEL, POOJA - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item FU, LONING - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item BERDEAUX, REBECCA - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item SUN, KAI - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item KOLONIN, MIKHAIL - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item WANG, SIDNEY - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item YOO, SEUNG-HEE - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item SLADEK, FRANCES - UNIVERSITY OF CALIFORNIA
item ECKEL-MAHAN, KRISTIN - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/18/2018
Publication Date: 10/19/2018
Citation: Fekry, B., Ribas-Latre, A., Baumgartner, C., Deans, J.R., Kwok, C., Patel, P., Fu, L., Berdeaux, R., Sun, K., Kolonin, M.G., Wang, S.H., Yoo, S., Sladek, F.M., Eckel-Mahan, K. 2018. Incompatibility of the circadian protein BMAL1 and HNF 4a in hepatocellular carcinoma. Nature Communications. https://doi.org/10.1038/s41467-018-06648-6.
DOI: https://doi.org/10.1038/s41467-018-06648-6

Interpretive Summary: Hepatocyte nuclear factor 4 alpha (HNF4a) is a master regulator of gene expression in the liver. Previous studies have revealed that HNF4a is required for suppressing hepatocellular carcinoma (HCC). However, many human HCCs still express HNF4a. In this study we found that in healthy hepatocytes HNF4a is a clock controlled gene and that the rhythmic expression of HNF4a is determined by its interaction with the circadian regulator ARNTL (BMAL1) over a 24 hour period. Many human HCCs, however, express an isoform of HNF4a, driven by an alternative promoter, which represses BMAL1 expression. We found that the expression of BMAL1 and the HNF4a isoform is mutual exclusive in HCC, and demonstrated that forced expression of BMAL1 in HNF4a-positive HCC prevents the growth of tumors in vivo. Our findings suggest that manipulation of the circadian clock in HNF4a-positive HCC could be a tractable strategy to inhibit HCC progression. The role of circadian control of HNF4a in HCC initiation and progression. The major messages delivered this article are that circadian regulator BMAL1 is a HCC suppressor and that HNF4a is one of the key tumor suppressor pathways directly targeted by BMAL1. Recent human epidemiological studies have revealed a strong link between chronic circadian disruption and increased risk of HCC. Our studies provided the first experimental evidence of the direct interaction of a circadian regulator with a key HCC suppression pathway. Further studies of the molecular mechanism controlling BMAL1- HNF4a interaction will lead to identification of novel therapeutic targets for HCC prevention and treatment.

Technical Abstract: Hepatocyte nuclear factor 4 alpha (HNF4a) is a master regulator of liver-specific gene expression with potent tumor suppressor activity, yet many liver tumors express HNF4a. This study reveals that P1-HNF4a, the predominant isoform expressed in the adult liver, inhibits expression of tumor promoting genes in a circadian manner. In contrast, an additional isoform of HNF4a, driven by an alternative promoter (P2-HNF4a), is induced in HNF4a-positive human hepatocellular carcinoma (HCC). P2-HNF4a represses the circadian clock gene ARNTL (BMAL1), which is robustly expressed in healthy hepatocytes, and causes nuclear to cytoplasmic re-localization of P1-HNF4a. We reveal mechanisms underlying the incompatibility of BMAL1 and P2-HNF4a in HCC, and demonstrate that forced expression of BMAL1 in HNF4a-positive HCC prevents the growth of tumors in vivo. These data suggest that manipulation of the circadian clock in HNF4a-positive HCC could be a tractable strategy to inhibit tumor growth and progression in the liver.