Cell-permeated peptide P-T3H2 inhibits malignancy on hepatocarcinoma through stabilizing HNF4α protein
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ABSTRACT:
PROVIDER: PRJNA1083871 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28227802_1.fastq.gz | Fastqsanger.gz | |||
| SRR28227802_2.fastq.gz | Fastqsanger.gz | |||
| SRR28227803_1.fastq.gz | Fastqsanger.gz | |||
| SRR28227803_2.fastq.gz | Fastqsanger.gz | |||
| SRR28227804_1.fastq.gz | Fastqsanger.gz |
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Project description:Objectives: Hepatocyte nuclear factor 4α (HNF4α) is a key regulator of hepatocyte function and has a strong therapeutic effect on hepatocellular carcinoma (HCC) by inducing the differentiation of hepatoma cell into hepatocytes. Our previous study showed that Tribbles homolog 3 (TRIB3) directly interacts with and promotes the degradation of HNF4α in non-alcoholic fatty liver disease (NAFLD). Disrupting the TRIB3-HNF4α interaction by using a cell-permeating peptide called P-T3H2 stabilizes HNF4α protein. This study aimed to assess the anti-tumor impact of P-T3H2 in HCC. Methods: The expression of TRIB3 and HNF4α was assessed using western blot and immunohistochemistry staining (IHC). Hepatic functions in HCC cells were evaluated through periodic acid-Schiff (PAS) staining and acetylated low-density lipoprotein (ac-LDL) uptake. Senescence-associated β-galactosidase (SA-β-gal) activity staining was used to detected the cellular senescence in HCC cells. RNA-Seq analysis was carried out to identify differentially expressed genes in Huh-7 cells treated with the peptide P-T3H2 compared to the control peptide P-T3H2-2A. The impact of P-T3H2 on hepatocarcinoma malignancy was evaluated in HCC cells, a Huh-7 xenograft mouse model, an orthotopic model, and a C-MET/ΔN90-β-catenin-driven HCC model. Results: TRIB3 exhibited a negative correlation with HNF4α in both human and mouse HCC tissues. The administration of P-T3H2 significantly inhibited the malignancy of HCC cells. Additionally, P-T3H2 stabilized the HNF4α protein and facilitated the restoration of hepatic functions and the cellular senescence in HCC cells. RNA-Seq analysis demonstrated that P-T3H2 enhanced the transcriptional activity of HNF4α in HCC. Furthermore, P-T3H2 effectively suppressed the growth of HCC tumors in both of the Huh7 xenograft and orthotopic mouse models in vivo. Notably, P-T3H2 also inhibits hepatocarcinogenesis in the C-MET/ΔN90-β-catenin-driven HCC model.
2024-12-18 | GSE260862 | GEO
Project description:ObjectivesHepatocyte nuclear factor 4α (HNF4α) is a key regulator of hepatocyte function and has a strong therapeutic effect on hepatocellular carcinoma (HCC) by inducing the differentiation of hepatoma cell into hepatocytes. Our previous study showed that Tribbles homolog 3 (TRIB3) directly interacts with and promotes the degradation of HNF4α in non-alcoholic fatty liver disease (NAFLD). Disrupting the TRIB3-HNF4α interaction by a cell-permeating peptide, called P-T3H2, stabilized HNF4α protein. This study aimed to assess the anti-tumor impact of P-T3H2 in HCC.MethodsThe expression of TRIB3 and HNF4α was evaluated using western blot and immunohistochemistry (IHC). Hepatic functions and cellular senescence of HCC cells were evaluated through periodic acid-Schiff (PAS) staining, acetylated low-density lipoprotein (ac-LDL) uptake and senescence-associated β-galactosidase (SA-β-gal) activity staining, respectively. RNA-Seq analysis was performed to identify differentially expressed genes in Huh7 cells treated with P-T3H2. The impact of P-T3H2 on HCC malignancy was assessed in vitro and in vivo.ResultsTRIB3 exhibited a negative correlation with HNF4α in both human and mouse HCC tissues. The administration of P-T3H2 significantly inhibited the malignancy of HCC cells. Additionally, P-T3H2 stabilized HNF4α protein and facilitated the restoration of hepatic functions and the cellular senescence in HCC cells. RNA-Seq analysis demonstrated that P-T3H2 enhanced the transcriptional activity of HNF4α in HCC. Furthermore, P-T3H2 effectively suppressed the carcinogenesis and progression of HCC in mice.ConclusionP-T3H2 suppressed HCC progression through the stabilization of HNF4α protein and may be a promising therapeutic candidate for clinical application in the treatment of HCC.
| S-EPMC11621286 | biostudies-literature
Project description:This project describes the mechanism by wich PRDX6 affects migration and invasiveness in hepatocarcinoma cells. SNU475 (mesenchymal) hepatocarcinoma cell line knockout for PRDX6 showed a marked increase in ROS and lipid peroxidation, mytochondrial dysfunction, metabolic reprogramming, altered cytoskeleton and activation of upstream regulators MYC, ATF4, HNF4A and HNF4G and inhibition of NRF2 and TP53. All these changes point to a role of PRDX6 in tumor development pointing to it as a candidate for antitumoral therapies.
2023-07-20 | PXD039491 | Pride
Project description:Background Worldwide, gastric cancer is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. Objective To determine oncogenic mechanisms and novel therapeutic targets specific for gastric cancer by identifying commonly dys-regulated genes from the tumors of both Asian-Pacific and Caucasian patients. Design We generated transcriptomic profiles of 22 Caucasian gastric cancer tumors and their matched non-cancerous samples, and performed an integrative analysis across different gastric cancer gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signaling pathways by RNAi and/or pharmacologic inhibition. Results We found that HNF4α upregulation was a key signaling event in gastric tumors from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumor cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signaling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest, and tumor growth inhibition. HNF4α also regulated WNT signaling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumors. Conclusions Our results indicate that HNF4α is a targetable oncoprotein in gastric cancer, is regulated by AMPK signaling through AMPKα, and resides upstream of WNT signaling. HNF4α may regulate “metabolic switch” characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signaling cascade represents a potentially targetable pathway for drug development. Integrative analysis of Caucasian and Asian-Pacific gastric tumor expression datasets (including newly generated transcriptomic profiling of 22 tumors in this study) revealed a relatively small common sets of highly overexpressed genes.
2014-11-15 | E-GEOD-63288 | biostudies-arrayexpress
Project description:Previous studies have highlighted the downregulation of hepatocyte nuclear factor 4α (HNF4α) as a critical event in the pathogenesis of HCC. However, the mechanism of its degradation in HCC remains unclear. Tripartite motif 47 (TRIM47), a typical E3 ubiquitin ligase of the TRIM family, implicates various tumors, yet its specific role in HCC progression is not fully elucidated. In this study, HNF4α was identified as a potential target of TRIM47 by using co-immunoprecipitation (Co-IP) combined with mass spectrometry analysis. TRIM47 facilitates the degradation of HNF4α by mediating K48-linked ubiquitination at lysine 470. Abrogation of HNF4α ubiquitination attenuated the promoting effect of TRIM47 on HCC malignancy. Molecular docking studies and Co-IP experiments revealed that K342, W349, and E353 of HNF4α, along with K534 and K600 of TRIM47 are crucial for their interaction. A small molecular, CZ-2401, was selected as a potent inhibitor of the TRIM47-HNF4α interaction through virtual screening and pharmacological activity validation. CZ-2401 effectively stabilizes HNF4α protein in HCC cells and ameliorates TRIM47-driven HCC progression in vivo. Taking together, our research elucidates that targeting TRIM47-HNF4α interaction is a potential therapeutic strategy for HCC, and identifies CZ-2401 as a potent inhibitor of HNF4α degradation and a promising candidate for HCC therapy.
2025-04-01 | PXD062446 |
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2023-01-26 | GSE184986 | GEO
Project description:Hepatocyte Nuclear Factor 4α (HNF4α), master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4α but not P2-HNF4α is expressed in normal adult liver while both P1- and P2-HNF4α are expressed in fetal liver and liver cancer. To determine the physiological function of the HNF4α isoforms, we compared P2-HNF4α-expressing exon swap mice to wildtype (WT) using RNA-seq, ChIP-seq, proteomics, protein binding microarrays (PBMs) and metabolomics. P2-HNF4α orchestrates a distinct transcriptomic and metabolomic profile.
2018-08-31 | GSE117972 | GEO
Project description:Hepatocyte Nuclear Factor 4α (HNF4α), master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4α but not P2-HNF4α is expressed in normal adult liver in fed conditions. Both P1- and P2-HNF4α are expressed in fetal liver. P2-HNF4α expression is increased in fasted conditions, high fat diet, alcoholic liver and liver cancer. To determine the target genes of the P1- and P2-HNF4α isoforms, we compared P2-HNF4α-expressing exon swap mice (a7HMZ) to wildtype (WT) male mice. Liver ChIP-seq samples were taken at 10:30 AM (ZT 3.5)
2023-05-10 | GSE231538 | GEO
Project description:Background Worldwide, gastric cancer is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. Objective To determine oncogenic mechanisms and novel therapeutic targets specific for gastric cancer by identifying commonly dys-regulated genes from the tumors of both Asian-Pacific and Caucasian patients. Design We generated transcriptomic profiles of 22 Caucasian gastric cancer tumors and their matched non-cancerous samples, and performed an integrative analysis across different gastric cancer gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signaling pathways by RNAi and/or pharmacologic inhibition. Results We found that HNF4α upregulation was a key signaling event in gastric tumors from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumor cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signaling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest, and tumor growth inhibition. HNF4α also regulated WNT signaling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumors. Conclusions Our results indicate that HNF4α is a targetable oncoprotein in gastric cancer, is regulated by AMPK signaling through AMPKα, and resides upstream of WNT signaling. HNF4α may regulate “metabolic switch” characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signaling cascade represents a potentially targetable pathway for drug development.
2014-11-15 | GSE63288 | GEO