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The Loss of an orphan Nuclear Receptor augments Wnt/β-Catenin signaling via epigenetic dysregulation that promotes Sp1 and Myc interactions in Hepatocellular Carcinoma Development [RNA-seq]

ABSTRACT: We previously reported that the nuclear receptor NR2E3 activates the tumor suppressor gene p53 by modulating chromatin accessibility. In this study, we further investigated the impact of NR2E3 deficiency on chromatin accessibility. We used FAIRE-seq (Formaldehyde-Assisted Isolation of Regulatory Elements) analysis to find that NR2E3 loss increased chromatin accessibility in genomic regions interacting with various transcription factors, including Sp1. Additionally, NR2E3 loss enhanced chromatin accessibility and expression of crucial genes, such as JAK1 and PPARD, essential for WNT-β-catenin signaling pathway activation by facilitating interactions between Sp1 and Myc transcription factors at their promoters. Gene set enrichment analysis (GSEA) on mouse liver tumor tissues from wild-type and NR2E3 knockout mice confirmed that NR2E3 ablation activated WNT-β-catenin signaling pathways in vivo. Kaplan-Meier survival analysis using liver cancer patient data from two clinical datasets confirmed that patients with low NR2E3 expression exhibited increased WNT-β-catenin signaling activation, associated with adverse clinical outcomes. These findings highlight NR2E3 as a crucial tumor suppressor gene in hepatocellular carcinoma (HCC), primarily restraining WNT-β-catenin signaling pathway activation to maintain epigenetic homeostasis and contribute to HCC development. Our results prove NR2E3's critical role in liver cancer pathogenesis by regulating WNT-β-catenin signaling pathways and epigenetic equilibrium maintenance. RNA-seq with WT and NR2E3 KO Liver Tumors

ORGANISM(S): Mus musculus

PROVIDER: GSE243017 | GEO | 2024/08/26

REPOSITORIES: GEO

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The Loss of an orphan Nuclear Receptor augments Wnt/β-Catenin signaling via epigenetic dysregulation that promotes Sp1 and Myc interactions in Hepatocellular Carcinoma Development [FAIRE-seq]

Project description:We previously reported that the nuclear receptor NR2E3 activates the tumor suppressor gene p53 by modulating chromatin accessibility. In this study, we further investigated the impact of NR2E3 deficiency on chromatin accessibility. We used FAIRE-seq (Formaldehyde-Assisted Isolation of Regulatory Elements) analysis to find that NR2E3 loss increased chromatin accessibility in genomic regions interacting with various transcription factors, including Sp1. Additionally, NR2E3 loss enhanced chromatin accessibility and expression of crucial genes, such as JAK1 and PPARD, essential for WNT-β-catenin signaling pathway activation by facilitating interactions between Sp1 and Myc transcription factors at their promoters. Gene set enrichment analysis (GSEA) on mouse liver tumor tissues from wild-type and NR2E3 knockout mice confirmed that NR2E3 ablation activated WNT-β-catenin signaling pathways in vivo. Kaplan-Meier survival analysis using liver cancer patient data from two clinical datasets confirmed that patients with low NR2E3 expression exhibited increased WNT-β-catenin signaling activation, associated with adverse clinical outcomes. These findings highlight NR2E3 as a crucial tumor suppressor gene in hepatocellular carcinoma (HCC), primarily restraining WNT-β-catenin signaling pathway activation to maintain epigenetic homeostasis and contribute to HCC development. Our results prove NR2E3's critical role in liver cancer pathogenesis by regulating WNT-β-catenin signaling pathways and epigenetic equilibrium maintenance. The Formaldehyde Assisted Isolation of Regulatory Elemens (FAIRE)-Seqwas performed using control (shCT) and NR2E3-depleted (shNR2E3) HepG2 cells.

2024-08-26 | GSE243019 | GEO

The loss of an orphan nuclear receptor NR2E3 augments Wnt/β-Catenin signaling via epigenetic dysregulation that promotes the Sp1-β catenin-p300 interactions in hepatocellular carcinoma.

Project description:The orphan nuclear receptor NR2E3 (Nuclear receptor subfamily 2 group E, Member 3) is an epigenetic player essential for p53 activation during liver injuries through its modulation of chromatin accessibility. Nonetheless, a precise tumor suppressive and epigenetic role of NR2E3 in hepatocellular carcinoma (HCC) remains unclear. HCC patients expressing low NR2E3 exhibit unfavorable clinical outcomes, aligning with heightened activation of the WNT/β-catenin signaling pathway. The murine HCC models utilizing NR2E3 knockout mice consistently exhibits accelerated liver tumor formation and progression accompanied by enhanced activation of WNT/β-catenin signaling pathway and inactivation of p53 signaling pathway. At cellular level, the loss of NR2E3 increases the acquisition of aggressive cancer cell phenotype and tumorigenicity and upregulates key genes in the WNT/β-catenin pathway with enhanced chromatin accessibility. This event is mediated through increased formation of active transcription complex involving Sp1, β-catenin, and p300, a histone acetyltransferase, on the promoters of target genes. These findings demonstrate that the loss of NR2E3 promotes WNT/β-catenin signaling activation at cellular, organismal, and clinical levels. In summary, NR2E3 is a novel tumor suppressor that maintains epigenetic homeostasis, thereby preventing activation of WNT/β-catenin signaling that promotes HCC formation and progression.

2024-08-26 | GSE243020 | GEO

ATAC-seq experiment at four time points in HEK293 and hESC cells, assessing the time-resolved response on chromatin accessibility upon Wnt/β-catenin signaling activation

Project description:Wnt/β-catenin signaling is a highly organized biochemical cascade that triggers a gene expression program in the signal-receiving cell. The Wnt/β-catenin -driven transcriptional response is involved in virtually all cellular processes during development, homeostasis, and its deregulation causes human disease. However, outstanding questions remain unanswered. Among these, one regards how the Wnt/β-catenin cascade modulates the chromatin behavior: to date, there exists no comprehensive genome-wide annotation of changing chromatin patterns upon Wnt pathway activation. This is important, as shifts in chromatin patterns might underlie how different cells promote diverging gene expression programs in response to Wnt. To address this question, we characterized how Wnt/β-catenin signaling shapes the genome-wide chromatin accessibility landscape in two human cell types, human embryonic kidney cells 293T (HEK293T) and human embryonic stem cells (hESCs), over time. To this end, we treated HEK293T and hESCs with the GSK3 inhibitor/Wnt activator CHIR99021 (10 mM) for 3 days and assessed chromatin accessibility via ATAC-sequencing 4 hours, 24 hours and 3 days after the onset of the stimulation. We found that hESCs respond to Wnt/β-catenin activation by progressively shaping their chromatin accessibility profile in a manner that is consistent with their gradual acquisition of a mesodermal identity: differentiation genes loci open over time, while pluripotency ones close. We refer to this genomic response as plastic. On the other hand, HEK293T, which are known to be highly responsive to Wnt activation, appear more resistant to a long-term Wnt/β-catenin-driven change in cell identity. In this context, the chromatin displays a temporary opening of relevant regions at 4 hours after stimulation, followed by a re-establishment of its pre-stimulation state: we define this transient response as elastic.

2022-09-30 | E-MTAB-12076 | biostudies-arrayexpress

Bulk transcriptomic analysis of two models of zebrafish beta-catenin-driven HCC

Project description:Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding β-catenin. β-catenin has dual cellular functions as a component of the Wnt signaling pathway and adherens junctions. HCC-associated CTNNB1 mutations stabilize the β-catenin protein, leading to nuclear and/or cytoplasmic localization of β-catenin and downstream activation of Wnt target genes. In patient HCC samples, β-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in β-catenin activation are not well understood. To define mechanisms of β-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated β-catenin in 1) a small number of hepatocytes in early development; or 2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated β-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/β-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish β-catenin-driven HCC. Ingenuity Pathway Analysis of differentially expressed genes in the Cre-lox HCC model revealed that “Cancer” and “Liver Tumor” categories were significantly altered, indicating transcriptional similarities with human HCC and other vertebrate HCC models. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish β-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca, and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous β-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis.

2019-09-27 | GSE137787 | GEO

Single-cell transcriptomic analysis of two models of zebrafish beta-catenin-driven HCC

2019-09-27 | GSE137784 | GEO

Role of bcatenin in hepatocellular carcinoma

Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. β-catenin is widely thought to be a major oncogene in HCC based on the frequency of mutations associated with aberrant Wnt signaling in HCC patients. Challenging this model, our data reveal that β-catenin nuclear accumulation is restricted to the late stage of the disease. Until then, β-catenin is primarily located at the plasma membrane in complex with multiple cadherin family members where it drives tumor cell survival by enhancing the signaling of growth factor receptors such as EGFR. Therefore, our study reveals the evolving nature of β-catenin in HCC to establish it as a compound tumor promoter during the progression of the disease.

2019-03-29 | PXD013095 | Pride

The protein kinase activity of NME7 activates one-carbon metabolism through positively regulating wnt/β-catenin signaling

Project description:Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/β-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the molecular mechanisms linked to hyperactivation of Wnt/β-catenin signaling and the strategy for targeting this pathway in HCC are incompletely understood. In this study, a screen of the potential kinases regulating Wnt/β-catenin signaling revealed that NME7 is a positive regulator of this pathway. NME7 was upregulated in HCC, and its expression was positively correlated with the clinical features of patients with HCC. Knockdown of NME7 inhibited the growth and tumorigenesis of HCC cells, while overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model of HCC established by hydrodynamic injection and promote the growth of tumor-derived organoids. Mechanistically, GSK3β was identified as the substrate of NME7, and their interaction was strengthened upon Wnt3a stimulation. NME7 exerts protein kinase activity and phosphorylates serine 9 of GSK3β in vitro and in vivo. Through further study, MTHFD2, the key enzyme in one-carbon metabolism, was found to be the target gene of β-catenin and to mediate the biological functions of NME7. Moreover, mouse tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to the MTHFD2 inhibitor LY345899. Additionally, the expression levels of NME7, β-catenin and MTHFD2 correlated well in HCC, and higher expression of all three predicted poor prognosis. Taken together, the results of this study emphasize the crucial roles of NME7 protein kinase activity in activating one-carbon metabolism and Wnt/β-catenin signaling, suggesting that NME7 and MTHFD2 are therapeutic targets for HCC.

2022-10-01 | GSE165985 | GEO

High frequency of β-catenin mutations in mouse HCCs induced by a non-genotoxic CAR agonist

Project description:Activation of Wnt/β-catenin signaling is frequent in human and rodent hepatocarcinogenesis. Although in mice, the tumor promoting activity of agonists of constitutive androstane receptor (CAR) occurs via selection of carcinogen-initiated cells harbouring β-catenin mutations, the molecular alterations leading to hepatocellular carcinoma (HCC) development by The CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), in the absence of genotoxic injury are unknown. Here we show that CAR activation per se induced HCC in mice and that 91% of them carried β-catenin point mutations or large in-frame deletions/exon skipping targeting Ctnnb1 exon 3. Point mutations in HCCs induced by TCPOBOP alone displayed different nucleotide substitutions compared to those found in HCCs from mice pre-treated with diethylnitrosamine (DENA). Moreover, unlike those occurring in HCCs from DENA+TCPOBOP mice, they did not result in increased expression of β-catenin target genes, such as Glul, Lgr5, Rgn, Lect2 and Ccnd1, or nuclear translocation of β-catenin when compared to the control liver. Remarkably, in the non-tumoral liver tissue, chronic CAR activation led to down-regulation of these genes and to a partial loss of glutamine synthetase (GS)-positive hepatocytes. These results thus show that while chronic CAR activation per se induces HCCs carrying β-catenin mutations, it concurrently down-regulates the Wnt/β-catenin pathway in non-tumoral liver. They also indicate that the relationship between CAR and β-catenin may be profoundly different between normal and neoplastic hepatocytes.

2018-04-27 | GSE113708 | GEO

Glucagon contributes to liver zonation in mice [Gcg infusion]

Project description:Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal function. Wnt/beta-catenin signaling controls metabolic zonation by activating genes in the perivenous hepatocytes, while suppressing genes in the periportal counterparts. We now demonstrate that glucagon opposes the actions of Wnt/beta-catenin signaling on gene expression and metabolic zonation pattern. The effects were more pronounced in the periportal hepatocytes where 28% of all genes were activated by glucagon and inhibited by Wnt/beta-catenin. The glucagon and Wnt/beta-catenin receptors and their signaling pathways are uniformly distributed in periportal and perivenous hepatocytes and the expression is not regulated by the opposing signal. Collectively, our results show that glucagon controls gene expression and metabolic zonation in the liver through a counter play with the Wnt/beta-catenin signaling pathway.

2018-03-01 | GSE110673 | GEO

Glucagon contributes to liver zonation in mice [Gcg KO]

2018-03-01 | GSE110672 | GEO

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