Loss of KDM6B confers resistance to lipotoxicity through epigenetic downregulation of G0S2 expression in NASH-related HCC
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PROVIDER: PRJNA872363 | ENA |
REPOSITORIES: ENA
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Project description:Background& Aims: The incidence of nonhepatitis B and nonhepatitis C viral (NBNC)- HCC has been rising in recent years due to the increase in NAFLD and NASH worldwide with fibrosis. However, the molecular mechanisms underlying the progression of these HCC are not fully understood. Here we observed that KDM6B, an H3K27 demethylase, was commonly downregulated in human NBNC-HCC and mouse NASH-related HCC by microarray analysis. The study aims to elucidate the molecular mechanism of KDM6B downregulation in NBNC-HCC including NASH-related HCC. Approach & Results: By immunohistochemistry, KDM6B expression was decreased in 28.7% of human HCC tissues, most of which were NBNC-HCC type. The low KDM6B expression group was accompanied by NASH in the adjacent liver. The KDM6B knockout (KO) HCC cells altered pathways of lipid metabolism by microarray and GSEA analysis. The KDM6B-KO cells significantly decreased lipid accumulation and cell reduction rates. Expression of two lipid-metabolism-related genes, G0S2 and ACSL1, were suppressed in the KDM6B-KO cells and the histone H3K27 trimethylation levels at the promoter regions were decreased when compared to the wild-type cells. Knockdown of G0S2 but not ACSL1 expression showed resistance to lipotoxicity in HCC cells. Moreover, inhibition of ATGL, a downstream target of G0S2, caused a decrease in lipid accumulation and cell proliferation. Conclusions: KDM6B regulates G0S2 expression via histone demethylation of its promoter region. Decreased KDM6B-dependent G0S2 expression through the histone modification pathway causes resistance to lipotoxicity, which may be involved in the carcinogenic mechanism of NASH-related HCC among NBNC-HCC.
2023-10-11 | GSE211848 | GEO
Project description:Non-alcoholic fatty liver disease is continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. Here, we integrated transcriptomic and chromatin accessibility analyses from human liver and mouse hepatocytes to identify lipotoxicity-sensitive transcription factors. We found that several transcription factors that were activated in liver from NASH patients and by mouse hepatocyte lipotoxicity. Notably, the gene expression linked to lipotoxicity closely correlated with transcriptional patters in fibrosis progression in NASH patients. Collectively, our findings uncovered novel molecular insights into lipotoxicity-induced NASH.
2022-07-13 | GSE173735 | GEO
Project description:Non-alcoholic fatty liver disease is continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. Here, we integrated transcriptomic and chromatin accessibility analyses from human liver and mouse hepatocytes to identify lipotoxicity-sensitive transcription factors. We found that several transcription factors that were activated in liver from NASH patients and by mouse hepatocyte lipotoxicity. Notably, the gene expression linked to lipotoxicity closely correlated with transcriptional patters in fibrosis progression in NASH patients. Collectively, our findings uncovered novel molecular insights into lipotoxicity-induced NASH.
2022-07-13 | GSE173734 | GEO
Project description:Non-alcoholic fatty liver disease is continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. Here, we integrated transcriptomic and chromatin accessibility analyses from human liver and mouse hepatocytes to identify lipotoxicity-sensitive transcription factors. We found that the transcription factors MAFK and TCF4 were activated in liver from NASH patients and by mouse hepatocyte lipotoxicity. Genetic deletion of these transcription factors protected hepatocytes against saturated fatty acid oversupply. Notably, MAFK- and TCF4-regulated gene expression linked to lipotoxicity closely correlated with transcriptional patters in fibrosis progression in NASH patients. Collectively, our findings uncovered novel molecular insights into lipotoxicityinduced NASH, revealing the relevance and therapeutic potential of MAFK and TCF4 in human disease.
2022-07-08 | PXD026717 | Pride
Project description:Limb expression 1-like protein (LIX1L) plays important role in various liver disorders, but its role and underlying mechanism in nonalcoholic hepatitis (NASH) and HCC progression remains obscure. Here, we report that LIX1L functions as a key integrative regulator linking lipid metabolism and inflammation, adipose tissue dysfunction and hepatic microenvironment reprogramming which promotes NASH progression. LIX1L significantly upregulated in NAFLD/NASH patients, mouse models and palmitic acid-stimulated hepatocytes. Lix1l deletion inhibits lipid deposition, inflammatory response and fibrosis in liver as well as adipocyte differentiation by downregulation of fatty acid translocase CD36 expression, alleviating NASH and associated HCC progression. In contrast, adeno-associated virus (AAV)-mediated LIX1L overexpression exacerbates NASH progression in mice. Mechanistically, metabolic stress promotes PARP1 mediated poly-ADP-ribosylation (PARylation) of LIX1L, subsequently increasing the stability and RNA binding ability of LIX1L protein. LIX1L binds to AU-rich element (ARE) in the 3’ untranslated region (UTR) of CD36 mRNA, thus attenuating CD36 mRNA decay. In NASH and associated HCC mouse models, LIX1L deficiency-mediated downregulation of CD36 suppresses adipogenesis, hepatic lipid uptake, and reprograms the tumor-prone liver microenvironment with increased cytotoxic T lymphocytes (CTLs), reduced immunosuppressive cell proportions. These data indicate a systematic function of LIX1L in the pathogenesis of NASH and underscore the PARP1/LIX1L/CD36 axis as a potential target for treatment of NASH and associated HCC.
2024-04-25 | GSE264479 | GEO
Project description:Genetic mutations in pancreatic ductal adenocarcinoma (PDAC) with critical roles have been well examined. The recent discovery of alterations in genes encoding histone modifiers suggests their possible roles in the complexity of cancer development. We previously reported loss of heterozygosity of the KDM6B gene, which encodes a histone demethylase for trimethylated histone H3 lysine 27 (H3K27me3), a repressive chromatin mark, in PDAC cells. In this study, we demonstrated that loss of KDM6B enhanced aggressiveness of PDAC cells. KDM6B has been regarded as a tumor suppressor that mediates oncogenic KRAS-induced senescence. Consistently, KDM6B was highly expressed in pancreatic precancerous lesions (pancreatic intraepithelial neoplasms); then, the expression decreased as the malignant grade progressed. We found that knockdown of KDM6B in PDAC cells promoted tumor sphere formation and increased peritoneal dissemination and liver metastasis in vivo. Microarray and chromatin immunoprecipitation analysis implicated CEBPA for aggressiveness induced by KDM6B knockdown. CEBPA knockdown recapitulated the phenotypic change of PDAC cells after KDM6B knockdown, which was reversed by forced expression of C/EBPα. Moreover, similar protein expression patterns of KDM6B and C/EBPα in human PDAC emphasized their functional correlation. Notably, pharmacological inhibition of the H3K27 methylase EZH2 in PDAC cells inhibited tumor sphere formation along with the upregulation of CEBPA expression, and this effect was impaired in KDM6B knockdown cells, highlighting the role for KDM6B in the activation of CEBPA. Together, our results propose a significant role for the KDM6B-C/EBPα axis in the PDAC phenotype.
2014-06-30 | GSE28155 | GEO
Project description:A comprehensive screening of site-specific N-glycopeptides in serum haptoglobin (Hp), a reporter molecule for aberrant glycosylation in HCC, has been performed to characterize glycopeptide markers for NASH-related HCCs.
2020-05-22 | PXD018502 | Pride
Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that can progress from simple fatty liver disease to non-alcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism and excretion (ADME) of drugs. Differential gene expression between three clinically defined pathological groups; normal, steatosis and NASH was analyzed. The samples were diagnosed as normal, steatotic, NASH with fatty liver (NASH fatty) and NASH without fatty liver (NASH NF). Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChipM-. Human 1.0ST arrays
2011-07-12 | E-MEXP-3291 | biostudies-arrayexpress
Project description:Paraffin-embedded paired tumor and peri-carcinoma tissues (n=4) were obtained from the Biorepository of Fudan University Institute of Liver Cancer, which were used for the Affymetrix microarray analysis To investigate the progression of NASH to HCC, we established a differential gene expression profile by analyzing significant expression changes in pathologically confirmed NASH-HCC and peri-carcinoma specimens using Affymetrix microarrays.
2020-06-01 | GSE99807 | GEO
Project description:Hepatocellular carcinoma (HCC) has dismal treatment responses to systemic therapies and is caused by both, viral and non-viral etiologies, including non-alcoholic steatohepatitis (NASH) 1–5. NASH - triggered by high caloric intake and sedentary lifestyle - has become an important driver for HCC development. Immunotherapy has been recently approved for HCC but stratification of responders versus non-responders has remained an unmet need 5–8. Here, we found a progressive accumulation of non-classical activated CD8+PD-1+ T-cells in livers of NASH-affected patients and mice. PD-L1/PD-1-targeted immunotherapy of NASH-induced HCC administered either at cancer-initiation or after cancer-establishment lacked beneficial effects in mice. On the contrary, PD-1-targeted immunotherapy drove hepatic necro-inflammation and increased liver cancer incidence, tumor number, and nodule size. Anti-CD8 or anti-CD8/anti-NK1.1 treatment suppressed liver cancer development, implicating CD8+ T-cells as liver cancer drivers in the context of NASH. In line, PD-1-/- mice challenged with a NASH-inducing diet displayed early-onset of liver cancer. Mechanistically, PD-1-targeted immunotherapy triggered necro-inflammation and a pro-tumorigenic environment in the context of NASH, increasing the abundance of hepatic TOX+CXCR6+ expressing CD8+PD-1+ TNF+ T-cells. Anti-CD8/anti-PD-1 or anti-TNF/anti-PD-1, but not anti-CD4/anti-PD-1 treatment reverted anti-PD1 treatment-related increase of liver inflammation, NASH severity and tumorigenesis. Gene expression profile and increased abundance of murine hepatic CD8+PD-1+ T-cells were corroborated in human CD8+PD-1+ T cells derived from NASH patients. In a meta-analysis of clinical trials testing PD-1-targeting immune checkpoint inhibitors alone (i.e. pembrolizumab) or in combination in 1656 patients with advanced HCC, immunotherapy was not favorable over to control treatment in non-viral- when compared to viral-related HCC. Similarly, in two clinical cohorts tested, patients with NASH-driven HCC had a significantly worse overall survival with PD-1-targeted immunotherapy than HCC patients with other etiologies. Our data identify non-viral etiologies, particularly NASH, as potentially non-responsive in the context of HCC immunotherapy, providing a strong rational basis for patient stratification.
2020-10-24 | GSE159977 | GEO