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Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma

Author

Listed:
  • 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)
    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)
    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)
    McGovern Medical School at the University of Texas Health Science Center (UT Health))

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.

Suggested Citation

  • 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 , 2018. "Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06648-6
    DOI: 10.1038/s41467-018-06648-6
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