Yes‐associated protein/TEA domain family member and hepatocyte nuclear factor 4‐alpha (HNF4α) repress reciprocally to regulate hepatocarcinogenesis in rats and mice

Cai, Wangyu; Lin, Lingyun; Han, Hao; Zhang, Sai-Man; Ma, Fei; Hong, Xinxin; Zhang, Hui; Li, Qingfeng; Ye, Guodong; Sun, Guangbin; Liu, Yunjia; Li, Shengnan; Xie, Yuanyuan; Cai, Jun; Li, Boan

doi:10.1002/hep.28911

Cited by 58 publications

(66 citation statements)

References 52 publications

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“…HNF4α is the master regulator of hepatocyte differentiation because it is required for hepatocyte differentiation during embryonic liver development and it maintains hepatocyte specific gene expression in adult hepatocytes (3)(4)(5). HNF4α also exerts strong anti-proliferative effects on hepatocytes and decreased HNF4α expression and activity results in loss of quiescence, which can lead to HCC (14,17,18). Despite being recognized as one of the strongest anti-proliferative proteins in the liver, the role of HNF4α during liver regeneration is not known.…”

Section: Discussionmentioning

confidence: 99%

“…Understanding the mechanisms that govern adult hepatocytes to navigate between quiescent and proliferative states could result in therapeutic targets for inducing hepatocyte proliferation during impaired regeneration or inhibiting excess proliferation during carcinogenesis. Despite its role in maintaining hepatocyte differentiation and quiescence, little is known about the role of HNF4α in hepatocyte regeneration or how decreased HNF4α, a condition commonly found in diseased human livers (9,(16)(17)(18), would impact regeneration. In this study, we investigated the role of HNF4α in regulation of liver regeneration after PH using wildtype (WT) and HNF4α-KO mice.…”

Section: Introductionmentioning

confidence: 99%

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Hepatocyte Nuclear Factor 4 alpha (HNF4α) Activation is Essential for Termination of Liver Regeneration

Huck

Gunewardena

Español–Suñer

et al. 2018

Preprint

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Hepatocyte Nuclear Factor 4 alpha (HNF4α) is critical for hepatic differentiation. Recent studies have highlighted its role in inhibition of hepatocyte proliferation and tumor suppression.However, the role of HNF4α in liver regeneration is not known. We hypothesized that hepatocytes modulate HNF4α activity when navigating between differentiated and proliferative states during liver regeneration. Western blot analysis revealed a rapid decline in nuclear and cytoplasmic HNF4α protein levels accompanied with decreased target gene expression within 1 hour after 2/3 partial hepatectomy (post-PH) in C57BL/6J mice. HNF4α protein expression did not recover to the pre-PH levels until day 3. Hepatocyte-specific deletion of HNF4α (HNF4α-KO) in mice resulted in 100% mortality post-PH despite increased proliferative marker expression throughout regeneration. Sustained loss of HNF4α target gene expression throughout regeneration indicated HNF4α-KO mice were unable to compensate for loss of HNF4α transcriptional activity. Deletion of HNF4α resulted in sustained proliferation accompanied by cmyc and cyclin D1 over expression and a complete deficiency of hepatocyte function after PH. Interestingly, overexpression of degradation-resistant HNF4α in hepatocytes did not prevent initiation of regeneration after PH. Finally, AAV8-mediated reexpression of HNF4α in hepatocytes of HNF4α-KO mice post-PH restored HNF4α protein levels, induced target gene expression and improved survival of HNF4α-KO mice post-PH. In conclusion, these data indicate that HNF4α reexpression following initial decrease is critical for hepatocytes to exit from cell cycle and resume function during the termination phase of liver regeneration. These results reveal the role of HNF4α in liver regeneration and have implications for therapy of liver failure.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hepatocyte Nuclear Factor 4 alpha (HNF4α) Activation is Essential for Termination of Liver Regeneration

Huck

Gunewardena

Español–Suñer

et al. 2018

Preprint

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“…Of these, three were consistently matched to each of our novel IAPs. The TEAD4 transcription factor has been linked to narcolepsy, a rare disorder involving the dysfunction of normal sleep patterns (Luca et al, ), as well as cancer cell development in animals (Cai et al, ) and humans (Suzuki et al, ). HMGA2 is linked to both obesity and type 2 diabetes mellitus in humans (Markowski et al, ), and in a murine knock out model HMGA2 was shown to be a necessary constituent of adipogenesis through its regulation of the relationship between CCAAT enhancer binding protein (C/EBP) and peroxisome‐proliferator activated receptor‐gamma (PPARγ) (Xi et al, ).…”

Section: Discussionmentioning

confidence: 99%

Perinatal lead (Pb) exposure results in sex and tissue‐dependent adult DNA methylation alterations in murine IAP transposons

Montrose

Faulk

Francis

et al. 2017

Environ and Mol Mutagen

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Epidemiological and animal data suggest that adult chronic disease is influenced by early-life exposure-induced changes to the epigenome. Previously, we observed that perinatal lead (Pb) exposure results in persistent murine metabolic- and activity-related effects. Using phylogenetic and DNA methylation analysis, we have also identified novel intracisternal A particle (IAP) retrotransposons exhibiting regions of variable methylation as candidate loci for environmental effects on the epigenome. Here, we now evaluate brain and kidney DNA methylation profiles of 4 representative IAPs in adult mice exposed to human physiologically-relevant levels of Pb two weeks prior to mating through lactation. When IAPs across the genome were evaluated globally, average (sd) methylation levels were 92.84% (3.74) differing by tissue (p<0.001), but not sex or dose. By contrast, the 4 individual IAPs displayed tissue-specific Pb and sex effects. Medium Pb-exposed mice had 3.86% less brain methylation at IAP 110 (p<0.01), while high Pb-exposed mice had 2.83% less brain methylation at IAP 236 (p=0.01) and 1.77% less at IAP 506 (p=0.05). Individual IAP DNA methylation differed by sex for IAP 110 in the brain and kidney, IAP 236 in the kidney, and IAP 1259 in the kidney. Using Tomtom, we identified 3 binding motifs that matched to each of our novel IAPs impacted by Pb, one of which (HMGA2) has been linked to metabolic-related conditions in both mice and humans. Thus, these recently identified IAPs display tissue-specific environmental lability as well as sex-specific differences supporting an epigenetic link between early exposure to Pb and later-in-life health outcomes.

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“…As the most important effectors, YAP1 and its closely related paralog TAZ act as oncogenes in various human cancers. Up-regulation of YAP1 has been observed in gastric cancer, colorectal cancer, squamous cell carcinoma (SCC), non-small cell lung cancer (NSCLC), ovarian cancer, uveal melanoma, endometrial cancer, hepatocellular cancer (HCC), pancreatic ductal adenocarcinoma, cholangiocarcinoma, and head and neck cancer [9,82,84,[90][91][92][93][94][95][96]. Meanwhile, overexpression of TAZ is observed in HCC, retinoblastoma, gastric cancer, colon cancer, NSCLC, ovarian cancer, endometrial cancer, osteosarcoma, glioma and oral cancer [84,94,[97][98][99][100][101][102][103][104][105][106].…”

Section: Yap1/taz Are Key Co-effectors Of the Hippo Pathway In Human mentioning

confidence: 99%

“…2). [12,14,15,89,134,136] Gastric cancer [8,84,124,132] Colorectal cancer [75,82,125,126] Squamous cell carcinoma [116] Non-small cell lung cancer [9,92,119] Ovarian cancer [11,85] Uveal melanoma [93] Endometrial cancer [94] Hepatocellular cancer [69,95,107,109,110] Pancreatic ductal adenocarcinoma [68,96] Cholangiocarcinoma [91] Head and neck cancer [90] Breast cancer [58,115] Malignant mesothelioma [70] Prostate cancer [86] Endometrial cancer [94] Medulloblastomas [114] Meningiomas [139] TAZ Hepatocellular cancer Proliferation, invasion, metastasis, higher clinical stage, shorter overall survival, disease recurrence, poor prognosis and chemotherapy resistance [97,107] Retinoblastoma [102] Gastric cancer [84,123] Colon cancer [82,101] Oral cancer…”

Section: Yap1/taz Are Key Co-effectors Of the Hippo Pathway In Human mentioning

confidence: 99%

Emerging role of Hippo signalling pathway in bladder cancer

Xia

Zeng

Zhu

et al. 2017

J Cellular Molecular Medi

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Bladder cancer (BC) is one of the most common cancers worldwide with a high progression rate and poor prognosis. The Hippo signalling pathway is a conserved pathway that plays a crucial role in cellular proliferation, differentiation and apoptosis. Furthermore, dysregulation and/or malfunction of the Hippo pathway is common in various human tumours, including BC. In this review, an overview of the Hippo pathway in BC and other cancers is presented. We focus on recent data regarding the Hippo pathway, its network and the regulation of the downstream co‐effectors YAP1/TAZ. The core components of the Hippo pathway, which induce BC stemness acquisition, metastasis and chemoresistance, will be emphasized. Additional research on the Hippo pathway will advance our understanding of the mechanism of BC as well as the development and progression of other cancers and may be exploited therapeutically.

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Yes‐associated protein/TEA domain family member and hepatocyte nuclear factor 4‐alpha (HNF4α) repress reciprocally to regulate hepatocarcinogenesis in rats and mice

Cited by 58 publications

References 52 publications

Hepatocyte Nuclear Factor 4 alpha (HNF4α) Activation is Essential for Termination of Liver Regeneration

Hepatocyte Nuclear Factor 4 alpha (HNF4α) Activation is Essential for Termination of Liver Regeneration

Perinatal lead (Pb) exposure results in sex and tissue‐dependent adult DNA methylation alterations in murine IAP transposons

Emerging role of Hippo signalling pathway in bladder cancer

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