Role of the histone methylase G9a in pancreatic carcinogenesis
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ABSTRACT:
PROVIDER: PRJNA627358 | ENA |
REPOSITORIES: ENA
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Project description:Accumulating evidences propose the importance of epigenetic regulation in pancreatic carcinogenesis, but the mechanistic insights of a variety of histone modification process still remains to be elucidated. G9a functions as a transcriptional repressor via the methylating activity specific for histone H3 lysine9. We identified G9a as a critical factor in the development of murine pancreatic oncogenesis.
2020-11-03 | GSE149093 | GEO
Project description:Histone methyltransferase G9a governs the mutant Kras-driven pancreatic carcinogenesis
| PRJNA635814 | ENA
Project description:Drosophila melanogaster G9a, G9a, is expressed in 3 baseline experiment(s);
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Project description:Drosophila melanogaster G9a, G9a, is differentially expressed in 11 experiment(s);
| FBgn0040372 | ExpressionAtlas
Project description:Background/aimThe entire mechanisms by which epigenetic modifiers contribute to the development of pancreatic cancer remain unknown. Although the histone methyltransferase G9a is a promising target in human cancers, its role in pancreatic carcinogenesis has been under-studied. The aim of the study was to examine the role of G9a in pancreatic carcinogenesis by a gene-targeting mouse model.Materials and methodsWe established pancreas-specific G9aflox/flox mice and crossed them with Ptf1aCre/; KrasG12D/+ (KC) mice, which spontaneously develop pancreatic cancer. The phenotypes of the resulting KC mice with G9a deletion were examined. We analyzed transcriptomic data by microarray and genome-wide chromatin accessibility by transposase-accessible chromatin using sequencing. We established pancreatic organoids from KC mice.ResultsG9a deficiency impaired the progression of pancreatic intraepithelial neoplasia (PanIN) and prolonged the survival of KC mice. The number of phosphorylated Erk-positive cells and Dclk1-positive cells, which are reported to be essential for the progression of PanIN, were decreased by G9a deletion. UNC0638, an inhibitor of G9a, suppressed the growth of organoids and increased global chromatin accessibility, especially around the regions including the protein phosphatase 2A genes.ConclusionThus, our study suggested the functional interaction of G9a, Dclk1 and Mapk pathway in the Kras-driven pancreatic carcinogenesis. The inhibition of G9a may suppress the initiation of oncogenic Kras-driven pancreatic carcinogenesis.
| S-EPMC7675651 | biostudies-literature
Project description:Epigenetic gene regulation in various oncogenic pathways is currently an important focus of cancer research. Histone modification plays a pivotal role in human carcinogenesis, but the significance of histone modification in hepatocarcinogenesis remains unknown. We used microarrays to investigate the oncogenic gene regulation by histone methylase G9a in chemically-induced murine hepatocellular carcinioma model.
2021-01-27 | GSE147061 | GEO
Project description:Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer’s disease proteopathology for precision medication
| PRJNA1165252 | ENA
Project description:we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment.
2025-03-18 | PXD047045 | Pride
Project description:Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality among adults in developed countries. The discovery of the most common genetic alterations as well as the development of organoids models of pancreatic cancer have provided insight into the fundamental pathways driving the progression from normal cell, to non-invasive precursor lesion, to widely metastatic disease, offering new opportunities for the discovery of key activated pathways along cancer progression. Obesity is one of the most serious public health challenges of the 21st century. Several epidemiological studies have shown the positive association between obesity and cancer-related morbidity/mortality, as well as poor prognosis and poorer treatment outcome. Despite strong evidence indicates a link between obesity and cancer incidence, the molecular basis of the initiating events remains largely elusive. This is mainly due to the lack of an accurate and reliable model of pancreatic carcinogenesis that mimics human obesity-associated PDAC, making data interpretation difficult and often confusing. Here we propose, to our knowledge, the best suitable and manageable preclinical tool, based on next-generation cell culture models, to study the effects of obesity on pancreatic carcinogenesis. Therefore we tracked the effects of obesity on the natural evolution of PDAC in a genetically-defined transplantable model of syngeneic murine pancreatic preneoplastic lesion (mP) and tumor (mT) derived organoids that recapitulates the progression of human disease from early preinvasive lesions to metastatic disease. Our models indicated that both genetic- and diet-induced obesity promoted incidence engraftment rate and growth of both preneoplastic and neoplastic organoids, favoring pancreatic cancer progression and distant metastases dissemination. Our obesity models of carcinogenesis mimic the evolution of human pancreatic cancer pathology, promoting carcinogenesis and concomitant accumulation of a myeloid infiltrate. These changes in cancer immune infiltrate were also associated to a specific pattern of anti-inflammatory Th2 signature. Moreover, gene expression profile analysis revealed a change in gene expression programs that addresses cells to different pancreatic subtypes and stromal conditions. Our results suggest that organoid-derived transplants in obese mice represent a suitable system to study early step of carcinogenesis and support the hypothesis that inflammation induced by obesity stimulates tumor progression and metastatization during pancreatic carcinogenesis.
2020-05-26 | PXD018362 | Pride
Project description:Regulatory T cells (Treg) are common in the tumor microenvironment in both human pancreatic cancer and in genetically engineered mouse models of the disease. Previous studies in orthotopic syngeneic models of pancreatic cancer -recapitulated in our own data- indicated that Treg depletion results CD8+ T cell-mediated tumor regression. In human patients and in mouse models, regulatory T cells accumulate during the onset of Pancreatic Intraepithelial Neoplasia (PanIN), the earliest steps of carcinogenesis. We thus generated a genetic model to investigate the role of regulatory T cells during the onset of pancreatic carcinogenesis. Unexpectedly, depletion of Tregs during early stages of carcinogenesis led to accelerated tumor progression.
2019-03-23 | GSE128707 | GEO