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      Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma

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          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.

          Abstract

          Hepatocyte nuclear factor 4 alpha (HNF4α) is regulated by different promoters to generate two isoforms, one of which functions as a tumor suppressor. Here, the authors reveal that induction of the alternative isoform in hepatocellular carcinoma inhibits the circadian clock by repressing BMAL1, and the reintroduction of BMAL1 prevents HCC tumor growth.

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          Most cited references47

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          Molecular architecture of the mammalian circadian clock.

          Circadian clocks coordinate physiology and behavior with the 24h solar day to provide temporal homeostasis with the external environment. The molecular clocks that drive these intrinsic rhythmic changes are based on interlocked transcription/translation feedback loops that integrate with diverse environmental and metabolic stimuli to generate internal 24h timing. In this review we highlight recent advances in our understanding of the core molecular clock and how it utilizes diverse transcriptional and post-transcriptional mechanisms to impart temporal control onto mammalian physiology. Understanding the way in which biological rhythms are generated throughout the body may provide avenues for temporally directed therapeutics to improve health and prevent disease. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis.

            The numerous functions of the liver are controlled primarily at the transcriptional level by the concerted actions of a limited number of hepatocyte-enriched transcription factors (hepatocyte nuclear factor 1alpha [HNF1alpha], -1beta, -3alpha, -3beta, -3gamma, -4alpha, and -6 and members of the c/ebp family). Of these, only HNF4alpha (nuclear receptor 2A1) and HNF1alpha appear to be correlated with the differentiated phenotype of cultured hepatoma cells. HNF1alpha-null mice are viable, indicating that this factor is not an absolute requirement for the formation of an active hepatic parenchyma. In contrast, HNF4alpha-null mice die during embryogenesis. Moreover, recent in vitro experiments using tetraploid aggregation suggest that HNF4alpha is indispensable for hepatocyte differentiation. However, the function of HNF4alpha in the maintenance of hepatocyte differentiation and function is less well understood. To address the function of HNF4alpha in the mature hepatocyte, a conditional gene knockout was produced using the Cre-loxP system. Mice lacking hepatic HNF4alpha expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations. The observed phenotypes may be explained by (i) a selective disruption of very-low-density lipoprotein secretion due to decreased expression of genes encoding apolipoprotein B and microsomal triglyceride transfer protein, (ii) an increase in hepatic cholesterol uptake due to increased expression of the major high-density lipoprotein receptor, scavenger receptor BI, and (iii) a decrease in bile acid uptake to the liver due to down-regulation of the major basolateral bile acid transporters sodium taurocholate cotransporter protein and organic anion transporter protein 1. These data indicate that HNF4alpha is central to the maintenance of hepatocyte differentiation and is a major in vivo regulator of genes involved in the control of lipid homeostasis.
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              Circadian Rhythm Disruption Promotes Lung Tumorigenesis.

              Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression.
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                Author and article information

                Contributors
                Kristin.L.Mahan@uth.tmc.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                19 October 2018
                19 October 2018
                2018
                : 9
                : 4349
                Affiliations
                [1 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Institute of Molecular Medicine, , McGovern Medical School at the University of Texas Health Science Center (UT Health), ; Houston, TX 77030 USA
                [2 ]ISNI 0000 0001 2222 1582, GRID grid.266097.c, Department of Molecular, Cell and Systems Biology, , University of California Riverside, ; Riverside, CA 92521 USA
                [3 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Pediatrics, Molecular and Cellular Biology, , Children’s Nutrition Research Center, Baylor College of Medicine, ; Houston, TX 77030 USA
                [4 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Department of Integrative Biology and Pharmacology, , McGovern Medical School at the University of Texas Health Science Center (UT Health), ; Houston, TX 77030 USA
                [5 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Department of Biochemistry and Molecular Biology, , McGovern Medical School at the University of Texas Health Science Center (UT Health), ; Houston, TX 77030 USA
                Author information
                http://orcid.org/0000-0002-3743-7869
                http://orcid.org/0000-0001-8201-1675
                Article
                6648
                10.1038/s41467-018-06648-6
                6195513
                30341289
                af08af61-2821-43c4-a0c3-ebc1aedd5bea
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 29 January 2018
                : 18 September 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: DK092590
                Award ID: DK053895
                Award ID: DK109001
                Award ID: DK09470
                Award ID: DK053895
                Award ID: DK114037
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000048, American Cancer Society (American Cancer Society, Inc.);
                Award ID: RSG-17-215-01-C
                Award Recipient :
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