Hepatocyte nuclear factor (HNF)-4α-driven epigenetic silencing of the human PED gene

Ungaro, Paola; Teperino, Raffaele; Mirra, Paola; Longo, Michele; Ciccarelli, Marco; Raciti, Gregory Alexander; Nigro, Cecilia; Miele, Claudia; Formisano, Pietro; Béguinot, Francesco

doi:10.1007/s00125-010-1732-x

Cited by 17 publications

(15 citation statements)

References 52 publications

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“…In the TCF4-HNF4a complex, HNF4a might mimic the Wnt turned-off status. In support of the last two mechanisms, published reports indicated that HNF4a associates with HDAC-containing SMRT complex to repress gene expression (Ruse et al, 2002;Ungaro et al, 2010). In this scenario, the TCF4-HNF4a complex may recruit the co-repressors through HNF4a or HNF4a and TCF4 together.…”

Section: Discussionmentioning

confidence: 85%

Double-negative feedback loop between Wnt/β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma

Meng

Anjum

et al. 2013

Journal of Cell Science

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SummaryWnt-b-catenin signaling participates in the epithelial-mesenchymal transition (EMT) in a variety of cancers; however, its involvement in hepatocellular carcinoma (HCC) and downstream molecular events is largely undefined. HNF4a is the most prominent and specific factor maintaining the differentiation of hepatic lineage cells and a potential EMT regulator in HCC cells. However, the molecular mechanisms by which HNF4a maintains the differentiated liver epithelium and inhibits EMT have not been completely defined. In this study, we systematically explored the relationship between Wnt-b-catenin signaling and HNF4a in the EMT process of HCC cells. Our results indicated that HNF4a expression was negatively regulated during Wnt-b-catenin signaling-induced EMT through Snail and Slug in HCC cells. In contrast, HNF4a was found to directly associate with TCF4 to compete with b-catenin but facilitate transcription corepressor activities, thus inhibiting expression of EMT-related Wnt-b-catenin targets. Moreover, HNF4a may control the switch between the transcriptional and adhesion functions of b-catenin. Overexpression of HNF4a was found to completely compromise the Wnt-b-catenin-signaling-induced EMT phenotype. Finally, we determined the regulation pattern between Wnt-b-catenin signaling and HNF4a in rat tumor models. Our studies have identified a double-negative feedback mechanism controlling Wnt-b-catenin signaling and HNF4a expression in vitro and in vivo, which sheds new light on the regulation of EMT in HCC. The modulation of these molecular processes may be a method of inhibiting HCC invasion by blocking Wnt-b-catenin signaling or restoring HNF4a expression to prevent EMT.

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Section: Discussionmentioning

confidence: 85%

Double-negative feedback loop between Wnt/β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma

Meng

Anjum

et al. 2013

Journal of Cell Science

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“…Mycoplasma contamination was not detected in L6 cells. Trichostatin A treatment and 2-deoxyglucose (2-DG) uptake were performed as previously reported [24,25].…”

Section: Methodsmentioning

confidence: 99%

“…Chromatin immunoprecipitation and re-chromatin immunoprecipitation assay procedures The chromatin immunoprecipitation (ChIP) assay was performed as described previously [24]. DNA fragments were recovered and subjected to PCR using the primer sequences described in ESM Table 1.…”

Section: Methodsmentioning

confidence: 99%

Glucose-induced expression of the homeotic transcription factor Prep1 is associated with histone post-translational modifications in skeletal muscle

et al. 2015

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“…Ungaro et al (34) provided some of the first evidence that HNF4␣ may function as a negative transcriptional regulator. Their data support the hypothesis that HNF4␣ negatively regulates expression of the preimplantation embryonic development (PED) gene in the liver.…”

mentioning

confidence: 99%

Hepatocyte-specific deletion of hepatocyte nuclear factor-4α in adult mice results in increased hepatocyte proliferation

Walesky

Gunewardena

Terwilliger

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

107

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Hepatocyte nuclear factor-4␣ (HNF4␣) is known as the master regulator of hepatocyte differentiation. Recent studies indicate that HNF4␣ may inhibit hepatocyte proliferation via mechanisms that have yet to be identified. Using a HNF4␣ knockdown mouse model based on delivery of inducible Cre recombinase via an adeno-associated virus 8 viral vector, we investigated the role of HNF4␣ in the regulation of hepatocyte proliferation. Hepatocyte-specific deletion of HNF4␣ resulted in increased hepatocyte proliferation. Global gene expression analysis showed that a majority of the downregulated genes were previously known HNF4␣ target genes involved in hepatic differentiation. Interestingly, Ն500 upregulated genes were associated with cell proliferation and cancer. Furthermore, we identified potential negative target genes of HNF4␣, many of which are involved in the stimulation of proliferation. Using chromatin immunoprecipitation analysis, we confirmed binding of HNF4␣ at three of these genes. Furthermore, overexpression of HNF4␣ in mouse hepatocellular carcinoma cells resulted in a decrease in promitogenic gene expression and cell cycle arrest. Taken together, these data indicate that, apart from its role in hepatocyte differentiation, HNF4␣ actively inhibits hepatocyte proliferation by repression of specific promitogenic genes. adeno-associated virus; Ect2; gene repression; hepatocyte proliferation; liver regeneration THE LIVER IS KNOWN for its exceptional capability to regenerate in response to surgical removal, as well as following druginduced liver injury. Liver regeneration is critical in maintaining liver health, because the liver is the major site of xenobiotic detoxification and is exposed to a variety of drugs and chemicals. The mechanisms of initiation and progression of liver regeneration are well studied, but the mechanisms of termination of regeneration are not completely understood (27). It is important to understand the mechanisms of termination of liver regeneration, because many of the pathways involved in stimulation of liver regeneration can be carcinogenic if left unchecked. It is known that the mechanisms of termination of regeneration are essential to maintain controlled liver growth and inhibit progression to hepatocellular carcinoma (HCC). However, the detailed mechanisms of termination of regeneration and their link to prevention of HCC are not completely clear.Hepatocyte nuclear factor-4␣ (HNF4␣, representative public ID NR2A1) is considered the master regulator of hepatocyte differentiation. It plays an important role in the regulation of many hepatocyte-specific genes, including those involved in glycolysis, gluconeogenesis, ureagenesis, fatty acid metabolism, bile acid synthesis, drug metabolism, apolipoprotein synthesis, and blood coagulation (11, 15, 18 -21). Recent studies suggest a novel role of HNF4␣ in the regulation of cell proliferation (8,9,11,12,15,23,26,29,36). Data indicate that HNF4␣ may have antiproliferative activity in human embryonic kidney cells and rat pancreatic beta cell...

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Hepatocyte nuclear factor (HNF)-4α-driven epigenetic silencing of the human PED gene

Abstract: These results show that HNF-4alpha serves as a scaffold protein for histone deacetylase activities, thereby inhibiting liver expression of genes including PED. Dysregulation of these mechanisms may lead to upregulation of the PED gene in type 2 diabetes.

Cited by 17 publications

References 52 publications

Double-negative feedback loop between Wnt/β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma

Double-negative feedback loop between Wnt/β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma

Glucose-induced expression of the homeotic transcription factor Prep1 is associated with histone post-translational modifications in skeletal muscle

Hepatocyte-specific deletion of hepatocyte nuclear factor-4α in adult mice results in increased hepatocyte proliferation

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