Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma

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 and Kristin Eckel-Mahan ()
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Baharan Fekry: McGovern Medical School at the University of Texas Health Science Center (UT Health)
Aleix Ribas-Latre: McGovern Medical School at the University of Texas Health Science Center (UT Health)
Corrine Baumgartner: McGovern Medical School at the University of Texas Health Science Center (UT Health)
Jonathan R. Deans: University of California Riverside
Christopher Kwok: McGovern Medical School at the University of Texas Health Science Center (UT Health)
Pooja Patel: Children’s Nutrition Research Center, Baylor College of Medicine
Loning Fu: Children’s Nutrition Research Center, Baylor College of Medicine
Rebecca Berdeaux: McGovern Medical School at the University of Texas Health Science Center (UT Health)
Kai Sun: McGovern Medical School at the University of Texas Health Science Center (UT Health)
Mikhail G. Kolonin: McGovern Medical School at the University of Texas Health Science Center (UT Health)
Sidney H. Wang: McGovern Medical School at the University of Texas Health Science Center (UT Health)
Seung-Hee Yoo: McGovern Medical School at the University of Texas Health Science Center (UT Health)
Frances M. Sladek: University of California Riverside
Kristin Eckel-Mahan: McGovern Medical School at the University of Texas Health Science Center (UT Health)

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06648-6

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