Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma

Fekry, Baharan; Ribas‐Latre, Aleix; Baumgartner, Corrine; Deans, Jonathan; Kwok, Christopher; Patel, Pooja; Fu, Loning; Berdeaux, Rebecca; Sun, Kai; Kolonin, Mikhail G.; Wang, Sidney H.; Yoo, Seung-Hee; Sladek, Frances M.; Eckel‐Mahan, Kristin

doi:10.1038/s41467-018-06648-6

Cited by 82 publications

(131 citation statements)

References 70 publications

(75 reference statements)

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“…Chronic jet lag caused disruption of hepatic cholesterol, bile acid, and xenobiotic metabolism via elevation of constitutive androstane receptor (CAR), which is a regulator of xenobiotic metabolism and associated with hepatocarcinogenesis, indicating the association of circadian rhythms with liver metabolism and HCC development . Another study has found negative correlation of expression levels between BMAL1 and HNF4α, which is important for hepatocyte fate determination and functions . HNF4α had circadian activities with rhythmic expression of downstream targets such as cyclin B1 and D1 in murine hepatocyte line AML12 cells .…”

Section: Functional Roles and Therapeutic Potentials Of Melatonin Andmentioning

confidence: 99%

“…Another study has found negative correlation of expression levels between BMAL1 and HNF4α, which is important for hepatocyte fate determination and functions . HNF4α had circadian activities with rhythmic expression of downstream targets such as cyclin B1 and D1 in murine hepatocyte line AML12 cells . Human HCC lines, HepG2, Hep3B, and Huh7 cells, expressed high levels of HNF4α and low levels of BMAL1, and overexpression of BMAL1 in HepG2 cells caused elevated apoptosis and decreased tumor growth in xenograft mouse models, indicating the roles of circadian rhythms in hepatocyte carcinogenesis …”

Section: Functional Roles and Therapeutic Potentials Of Melatonin Andmentioning

confidence: 99%

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Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Sato

Meng

Francis

et al. 2020

Journal of Pineal Research

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Circadian rhythms and clock gene expressions are regulated by the suprachiasmatic nucleus in the hypothalamus, and melatonin is produced in the pineal gland. Although the brain detects the light through retinas and regulates rhythms and melatonin secretion throughout the body, the liver has independent circadian rhythms and expressions as well as melatonin production. Previous studies indicate the association between circadian rhythms with various liver diseases, and disruption of rhythms or clock gene expression may promote liver steatosis, inflammation, or cancer development. It is well known that melatonin has strong antioxidant effects. Alcohol drinking or excess fatty acid accumulation produces reactive oxygen species and oxidative stress in the liver leading to liver injuries. Melatonin administration protects these oxidative stress‐induced liver damage and improves liver conditions. Recent studies have demonstrated that melatonin administration is not limited to antioxidant effects and it has various other effects contributing to the management of liver conditions. Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases. This review summarizes recent findings for the functional roles and therapeutic potentials of circadian rhythms and melatonin in liver diseases.

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Section: Functional Roles and Therapeutic Potentials Of Melatonin Andmentioning

confidence: 99%

Section: Functional Roles and Therapeutic Potentials Of Melatonin Andmentioning

confidence: 99%

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Sato

Meng

Francis

et al. 2020

Journal of Pineal Research

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“…Even though the full compendium of TFs involved in promoting these enhancer landscape changes have not been fully characterized yet, HNF4A binding sites are highly enriched near genes downregulated in hepatocellular carcinomas (Ramaker et al, ), in line with work implicating this core hepatic TF in tumour suppression (Fekry et al, ; B.‐F. Ning et al, ; Yin et al, ).…”

Section: Nafld‐associated Remodeling Of Liver Gene Regulatory Landscapesmentioning

confidence: 86%

“…Forced re‐expression of HNF4A in a rat model of hepatic failure induced expression of other hepatic TFs and reversed fatal liver failure by restoring hepatocyte function (Nishikawa et al, ). Moreover, several studies indicate the tumor suppressor role of HNF4A in hepatocellular carcinomas (Yin et al, ; Fekry et al, ; B.‐F. Ning et al, ).…”

Section: Liver Cis‐regulatory Networkmentioning

confidence: 99%

Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease

Cebola

2020

WIREs Mechanisms of Disease

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Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) result from complex interactions between intrinsic and extrinsic factors, including genetics and exposure to obesogenic environments. These risk factors converge in aberrant gene expression patterns in the liver, which are underlined by altered cis‐regulatory networks. In homeostasis and in disease states, liver cis‐regulatory networks are established by coordinated action of liver‐enriched transcription factors (TFs), which define enhancer landscapes, activating broad gene programs with spatiotemporal resolution. Recent advances in DNA sequencing have dramatically expanded our ability to map active transcripts, enhancers and TF cistromes, and to define the 3D chromatin topology that contains these elements. Deployment of these technologies has allowed investigation of the molecular processes that regulate liver development and metabolic homeostasis. Moreover, genomic studies of NAFLD patients and NAFLD models have demonstrated that the liver undergoes pervasive regulatory rewiring in NAFLD, which is reflected by aberrant gene expression profiles. We have therefore achieved an unprecedented level of detail in the understanding of liver cis‐regulatory networks, particularly in physiological conditions. Future studies should aim to map active regulatory elements with added levels of resolution, addressing how the chromatin landscapes of different cell lineages contribute to and are altered in NAFLD and NAFLD‐associated metabolic states. Such efforts would provide additional clues into the molecular factors that trigger this disease. This article is categorized under: Biological Mechanisms > Metabolism Biological Mechanisms > Regulatory Biology Laboratory Methods and Technologies > Genetic/Genomic Methods

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“…Among those downregulated genes in sh-LINP1 cells, HNF4α, which has been reported to affect cell proliferation in several cancers, [12][13][14][15] was significantly overexpressed in AML patients while downregulated in CR patients ( Figure 2D). Therefore, HNF4α expression was positively correlated with LINP1 ( Figure 2E).…”

Section: Linp1 Regulated Hnf4α Signaling To Promote Aml Cell Survivalmentioning

confidence: 95%

LncRNA LINP1 regulates acute myeloid leukemia progression via HNF4α/AMPK/WNT5A signaling pathway

Shi

Dai

Chen

et al. 2019

Hematological Oncology

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LncRNAs play critical roles in various pathophysiological and biological processes, such as protein translation, RNA splicing, and epigenetic modification. Indeed, abundant evidences demonstrated that lncRNA act as competing endogenous RNAs (ceRNAs) to participate in tumorigenesis. However, little is known about the underlying function of lncRNA in nonhomologous end joining (NHEJ) pathway 1 (LINP1) in pediatric and adolescent acute myeloid leukemia (AML). The expression of LINP1 was examined in AML patient samples by qRT‐PCR. Cell proliferation was examined by CCK‐8 and Edu assays. β‐Galactosidase senescence assay, mGlucose uptake assay, lactate production assay, and Gene Ontology (GO) analysis were performed for functional analysis. We found that LINP1 was significantly overexpressed in AML patients at diagnosis, whereas downregulated after complete remission (CR). Furthermore, knockdown of LINP1 expression remarkably suppressed glucose uptake and AML cell maintenance. Mechanistically, LINP1 was found to inhibit the glucose metabolism by suppressing the expression of HNF4a. Both LINP1 and HNF4a knockdown reduced the expression levels of AMPK phosphorylation and WNT5A, indicating for the first time that LINP1 strengthened the HNF4a‐AMPK/WNT5A signaling pathway involved in cell glucose metabolism modulation and AML cell survival. Taken together, our results indicated that LINP1 promotes the malignant phenotype of AML cells and stimulates glucose metabolism, which can be regarded as a potential prognostic marker and therapeutic target for AML.

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Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma

Cited by 82 publications

References 70 publications

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease

LncRNA LINP1 regulates acute myeloid leukemia progression via HNF4α/AMPK/WNT5A signaling pathway

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