Hepatocyte nuclear factor 4α is required for cell differentiation and homeostasis in the adult mouse gastric epithelium

Moore, Ben D.; Khurana, Sakshi; Huh, Won Jae; Mills, Jason C.

doi:10.1152/ajpgi.00195.2016

Cited by 27 publications

(22 citation statements)

References 51 publications

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“…Besides cancer, previous studies have shown that HNF4α also functions in non-malignant tissues. In the mouse gastric epithelium, HNF4α is expressed in foveolar cells, mucous neck cells and zymogenic chief cells, where it regulates the ordered progression of mucous neck cells to zymogenic chief cells 29. In the human stomach, HNF4α is highly expressed in foveolar cells but not in chief cells and parietal cells 9.…”

Section: Discussionmentioning

confidence: 99%

HNF4αpathway mapping identifies wild-typeIDH1as a targetable metabolic node in gastric cancer

Ooi

Qamra

et al. 2019

Gut

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ObjectiveGastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that hepatocyte nuclear factor-4α (HNF4α) is specifically overexpressed in GC and functionally required for GC development. In this study, we investigated, on a genome-wide scale, target genes of HNF4α and oncogenic pathways driven by HNF4α and HNF4α target genes.DesignWe performed HNF4α chromatin immunoprecipitation followed by sequencing across multiple GC cell lines, integrating HNF4α occupancy data with (epi)genomic and transcriptome data of primary GCs to define HNF4α target genes of in vitro and in vivo relevance. To investigate mechanistic roles of HNF4α and HNF4α targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments.ResultsGene expression analysis across 19 tumour types revealed HNF4α to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top HNF4α-regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 (IDH1) emerged as a convergent HNF4α direct target gene regulating GC metabolism. We show that wild-type IDH1 is essential for GC cell survival, and that certain GC cells can be targeted by IDH1 inhibitors.ConclusionsOur results highlight a role for HNF4α in sustaining GC oncogenic metabolism, through the regulation of IDH1. Drugs targeting wild-type IDH1 may thus have clinical utility in GCs exhibiting HNF4α overexpression, expanding the role of IDH1 in cancer beyond IDH1/2 mutated malignancies.

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Section: Discussionmentioning

confidence: 99%

HNF4αpathway mapping identifies wild-typeIDH1as a targetable metabolic node in gastric cancer

Ooi

Qamra

et al. 2019

Gut

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“…We observed for the first time that the increase in expression and activity of HNF4α during differentiation led to the transcriptional upregulation of two of the three primary ER stress mediators: XBP1 and ATF6. HNF4α, which is considered to be important in the development of endodermal organs, is also required for continued maintenance of XBP1 in differentiated, adult cells . Analysis of a publicly available ChIP‐Sequencing dataset (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE23436) indicated that the only gene that showed promoter enrichment for HNF4α in the differentiated Caco‐2 cells that was common to the GO terms ER stress, cell differentiation, and autophagy (please see below for further discussions on autophagy) was XBP1 .…”

Section: Discussionmentioning

confidence: 99%

Enhanced expression of HNF4α during intestinal epithelial differentiation is involved in the activation of ER stress

et al. 2019

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Intestinal epithelial cells are derived from stem cells at the crypts that undergo differentiation into transit‐amplifying cells, which in turn form terminally differentiated enterocytes as these cells reach the villus. Extensive alterations in both transcriptional and translational programs occur during differentiation, which can induce the activation of cellular stress responses such as ER stress‐related unfolded protein response (UPR) and autophagy, particularly in the cells that are already committed to becoming absorptive cells. Using an epithelial cell model of enterocyte differentiation, we report a mechanistic study connecting enterocyte differentiation to UPR and autophagy. We report that differentiated colon epithelial cells showed increased cytosolic Ca2+ levels and activation of all three pathways of UPR: inositol‐requiring enzyme 1 (IRE1), protein kinase RNA‐like ER kinase, and activating transcription factor 6 (ATF6) compared to the undifferentiated cells. Enhanced UPR in the differentiated cells was accompanied by the induction of autophagy as evidenced by increased ratio of light chain 3 II/I, upregulation of Beclin‐1, and downregulation of p62. We show for the first time that mechanistically, the upregulation of hepatocyte nuclear factor 4α (HNF4α) during differentiation led to increased promoter binding and transcriptional upregulation of two major proteins of UPR: X‐box binding protein‐1 and ATF6, implicating HNF4α as a key regulator of UPR response during differentiation. Integrating wet‐lab with in silico analyses, the present study links differentiation to cellular stress responses, and highlights the importance of transcription factor signaling and cross‐talk between the cellular events in the regulation of intestinal cell differentiation.

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“…Once isthmus, neck and base are determined by the end of the third postnatal week (weaning period), mucous neck cells are more numerous and found among parietal cells 3 , which are pivotal for maintenance of the area 32 . Part of MNC population differentiates into ZC 7 14 , and such change depends on the activity of hepatocyte nuclear factor 4 α 37 , which controls transcription factor XBP1 (organization of rER) 38 that directly regulates Mist1 (establishment of apical secretory apparatus) 33 .…”

Section: Discussionmentioning

confidence: 99%

Corticosterone activity during early weaning reprograms molecular markers in rat gastric secretory cells

Zulian

Hosoya

Figueiredo

et al. 2017

Sci Rep

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Gastric epithelial cells differentiate throughout the third postnatal week in rats, and become completely functional by weaning time. When suckling is interrupted by early weaning (EW), cell proliferation and differentiation change in the gastric mucosa, and regulatory mechanisms might involve corticosterone activity. Here we used EW and RU486 (glucocorticoid receptor antagonist) to investigate the roles of corticosterone on differentiation of mucous neck (MNC) and zymogenic cells (ZC) in rats, and to evaluate whether effects persisted in young adults. MNC give rise to ZC, and mucin 6, Mist1, pepsinogen a5 and pepsinogen C are produced to characterize these cells. We found that in pups, EW augmented the expression of mucins, Mist1 and pepsinogen C at mRNA and protein levels, and it changed the number of MNC and ZC. Corticosterone regulated pepsinogen C expression, and MNC and ZC distributions. Further, the changes on MNC population and pepsinogen C were maintained until early- adult life. Therefore, by using EW as a model for altered corticosterone activity in rats, we demonstrated that the differentiation of secretory epithelial cells is sensitive to the type of nutrient in the lumen. Moreover, this environmental perception activates corticosterone to change maturation and reprogram cellular functions in adulthood.

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Hepatocyte nuclear factor 4α is required for cell differentiation and homeostasis in the adult mouse gastric epithelium

Cited by 27 publications

References 51 publications

HNF4αpathway mapping identifies wild-typeIDH1as a targetable metabolic node in gastric cancer

HNF4αpathway mapping identifies wild-typeIDH1as a targetable metabolic node in gastric cancer

Enhanced expression of HNF4α during intestinal epithelial differentiation is involved in the activation of ER stress

Corticosterone activity during early weaning reprograms molecular markers in rat gastric secretory cells

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