Differential Effects of Hepatocyte Nuclear Factor 4α Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells

Vuong, Linh; Chellappa, Karthikeyani; Dhahbi, Joseph M.; Deans, Jonathan; Fang, Bin; Bolotin, Eugene; Titova, N.V.; Hoverter, Nate P.; Spindler, Stephen R.; Waterman, Marian L.; Sladek, Frances M.

doi:10.1128/mcb.00030-15

Cited by 58 publications

(87 citation statements)

References 107 publications

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“…Interestingly, a higher level of HNF4α was also associated with a lower level of Axin2 , a positive target of β‐catenin (Figure F). This corroborates previous studies performed by our laboratory and others suggesting that HNF4α could impair β‐catenin signalling . Altogether, these data suggest that loss of HNF4α in pretumoural hepatocytes with β‐catenin activation could play a part during hepatocarcinogenesis.…”

Section: Resultssupporting

confidence: 92%

“…This corroborates previous studies performed by our laboratory and others suggesting that HNF4α could impair β-catenin signalling. 8,12,21,25 Altogether, these data suggest that loss of HNF4α in pretumoural hepatocytes with β-catenin activation could play a part during hepatocarcinogenesis.…”

Section: Hnf4α Expression Was Impaired During Liver Carcinogenesis mentioning

confidence: 73%

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The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β‐catenin activation

Sartor

Bachelot

Lager

et al. 2019

Liver International

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Background & Aims Loss of hepatocyte nuclear factor‐4α (HNF4α), a critical factor driving liver development and differentiation, is frequently associated with hepatocellular carcinoma (HCC). Our recent data revealed that HNF4α level was decreased in mouse and human HCCs with activated β‐catenin signalling. In addition, increasing HNF4α level by miR‐34a inhibition slowed tumour progression of β‐catenin‐activated HCC in mice. Methods We generated a Hnf4aflox/flox/Apcflox/flox/TTR‐CreERT2 (Hnf4a/Apc∆Hep) mouse line and evaluated the impact of Hnf4a disruption on HCC development and liver homoeostasis. Results There was no significant impact of Hnf4a disruption on tumour onset and progression in Apc∆Hep model. However, we observed an unexpected phenotype in 28% of Hnf4a∆Hep mice maintained in a conventional animal facility, which presented disorganized portal triads, characterized by stenosis of the portal vein and increased number and size of hepatic arteries and bile ducts. These abnormal portal structures resemble the human idiopathic non‐cirrhotic portal hypertension syndrome. We correlated the presence of portal remodelling with a higher expression of protein and mRNA levels of TGFβ and BMP7, a key regulator of the TGFβ‐dependent endothelial‐to‐mesenchymal transition. Conclusion These data demonstrate that HNF4α does not play a major role during β‐catenin‐driven HCC, thus revealing that the tumour suppressor role of HNF4α is far more complex and dependent probably on its temporal expression and tumour context. However, HNF4α loss in adult hepatocytes could induce abnormal portal structures resembling the human idiopathic non‐cirrhotic portal hypertension syndrome, which may result from endothelial‐ and epithelial‐to‐mesenchymal transitions.

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Section: Resultssupporting

confidence: 92%

Section: Hnf4α Expression Was Impaired During Liver Carcinogenesis mentioning

confidence: 73%

The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β‐catenin activation

Sartor

Bachelot

Lager

et al. 2019

Liver International

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“…The activation function 1 (AF‐1) domain at the N ‐terminus depicts the major difference between the P1‐HNF4α and P2‐HNF4α. The P2‐HNF4α lacks the AF‐1 domain and therefore is weaker than P1‐HNF4α regarding the transactivation activity . Additionally, P1‐HNF4α and P2‐HNF4α also differ in terms of tissue distribution.…”

Section: Introductionmentioning

confidence: 99%

“…Downregulation of P1‐HNF4α has been reported in hepatocellular carcinoma (HCC), colorectal carcinoma, and gastric carcinoma, during which P2 products are aberrantly elevated . P2‐HNF4α has been shown to promote inflammation and carcinogenesis in colon …”

Section: Introductionmentioning

confidence: 99%

Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α

Guo

Lü

2018

J of Cellular Biochemistry

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Hepatocyte nuclear factor 4α (HNF4α) is a master regulator of development and function of digestive tissues. The HNF4A gene uses two separate promoters P1 and P2, with P1 products predominant in adult liver, whereas P2 products prevalent in fetal liver, pancreas, and liver/colon cancer. To date, the mechanisms for the regulation of HNF4A and the dynamic switch of P1-HNF4α and P2-HNF4α during ontogenesis and carcinogenesis are still obscure. Our study validated the previously reported self-stimulation of P1-HNF4α but invalidated the reported synergism between HNF4α and HNF1α. HNF4A-AS1, a long noncoding RNA, is localized between the P2 and P1 promoters of HNF4A. We identified critical roles of P1-HNF4α in regulating the expression of HNF4A-AS1 and its mouse ortholog Hnf4a-os. Paired box 6 (PAX6), a master regulator of pancreas development overexpressed in colon cancer, cooperated with HNF1α to induce P2-HNF4α but antagonized HNF4α in HNF4A-AS1 expression. Thus, PAX6 may be important in determining ontogenic and carcinogenic changes of P2-HNF4α and HNF4A-AS1 in the pancreas and intestine. We also interrogated transactivation activities on multiple gene targets by multiple known and novel HNF4α mutants identified in patients with maturity onset diabetes of the young 1 (MODY1) and liver cancer. Particularly, HNF4α-D78A and HNF4α-G79S, two mutants found in liver cancer with mutations in DNA-binding domain, displayed highly gene-specific transactivation activities. Interestingly, HNF4α-Q277X, a MODY1 truncation mutant, antagonized the transactivation activities of HNF1α and farnesoid X receptor, key regulators of insulin secretion. Taken together, our study provides novel mechanistic insights regarding the transcriptional regulation and transactivation activity of HNF4α in digestive tissues.

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“…For example, it was previously shown that HNF4A and TCF4 recognize considerable numbers of common DNA sequences and compete together to regulate the expression of these shared genes [82]. It is possible that this may be occurring for Hnf4a and Tcf3 TFs, and since we found the hepatic-specific factor Hnf4a to be up-regulated and Tcf3 to be down-regulated, the direct reprogramming process might be favored (Fig 4B and 4C).…”

Section: Discussionmentioning

confidence: 69%

Role of Hepatic-Specific Transcription Factors and Polycomb Repressive Complex 2 during Induction of Fibroblasts to Hepatic Fate

et al. 2016

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Direct reprogramming using defined sets of transcription factors (TFs) is a recent strategy for generating induced hepatocytes (iHeps) from fibroblasts for use in regenerative medicine and drug development. Comprehensive studies detailing the regulatory role of TFs during this reprogramming process could help increase its efficiency. This study aimed to find the TFs with the greatest influences on the generation of iHeps from fibroblasts, and to further understand their roles in the regulation of the gene expression program. Here, we used systems biology approaches to analyze high quality expression data sets in combination with TF-binding sites data and protein-protein interactions data during the direct reprogramming of fibroblasts to iHeps. Our results revealed two main patterns for differentially expressed genes (DEGs): up-regulated genes were categorized as hepatic-specific pattern, and down-regulated genes were categorized as mesoderm- and fibroblast-specific pattern. Interestingly, hepatic-specific genes co-expressed and were regulated by hepatic-specific TFs, specifically Hnf4a and Foxa2. Conversely, the mesoderm- and fibroblast-specific pattern was mainly silenced by polycomb repressive complex 2 (PRC2) members, including Suz12, Mtf2, Ezh2, and Jarid2. Independent analysis of both the gene and core regulatory network of DE-TFs showed significant roles for Hnf4a, Foxa2, and PRC2 members in the regulation of the gene expression program and in biological processes during the direct conversion process. Altogether, using systems biology approaches, we clarified the role of Hnf4a and Foxa2 as hepatic-specific TFs, and for the first time, introduced the PRC2 complex as the main regulator that favors the direct reprogramming process in cooperation with hepatic-specific factors.

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Differential Effects of Hepatocyte Nuclear Factor 4α Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells

Cited by 58 publications

References 107 publications

The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β‐catenin activation

The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β‐catenin activation

Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α

Role of Hepatic-Specific Transcription Factors and Polycomb Repressive Complex 2 during Induction of Fibroblasts to Hepatic Fate

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