Project description:Genomic sequencing of hepatocellular carcinoma (HCC) uncovers a paucity of actionable mutations, underscoring the necessity to exploit epigenetic vulnerabilities for therapeutics. In HCC, EZH2-mediated H3K27me3 represents a major oncogenic chromatin modification, but how it modulates the therapeutic vulnerability of signaling pathways remains unknown. Here, we identified that EZH2 maintains H3K27 methylome through epigenetic silencing of specific gene sets. ChIP-seq revealed enrichment of EZH2/H3K27me3 at silenced loci in HBx-transgenic (TG) mouse-derived HCCs, including tumor suppressors whose down-regulation significantly correlated with EZH2 overexpression and poor survival of HCC patients. Defining the aberrant chromatin landscape of HCC sheds light into the mechanistic basis of effective EZH2-targeted inhibition.

2018-07-02 | GSE113326 | GEO

Dynamic changes in the epigenetic landscape are mandatory for acinar cell reprogramming and pancreatic carcinogenesis [ChIP-seq]

Project description:Pancreatic acinar cell reprogramming is described as a common hallmark in pancreatic regeneration and carcinogenesis, although the regulatory mechanisms are barely understood. To overcome limitations of cellular diversity posed by heterogeneous cell compositions and high stroma density in pathogenic tissue specimens, we have established a pure in vitro system mimicking the pancreatic carcinogenic sequence. With this model, we globally profiled for epigenetic and transcriptional alterations and demonstrate that regulatory key players and structural genes are extensively regulated by epigenetic mechanisms. A conditional knockout of the epigenetic repressor Ring1b showed that particularly the epigenetic silencing of acinar differentiation genes is a crucial step in acinar cell reprogramming and pancreatic cancer development. Moreover, a persistent epigenetic repression of these genes manifests tumor cell malignancy. Depletion or drug-dependent inhibition of Ring1b promoted tumor cell reprogramming towards a less aggressive phenotype offering new options for therapeutic intervention.

2019-04-23 | GSE116151 | GEO

Dynamic changes in the epigenetic landscape are mandatory for acinar cell reprogramming and pancreatic carcinogenesis [microarray]

2019-04-23 | GSE116150 | GEO

Loss of tumor suppressor IGFBP4 drives epigenetic reprogramming in hepatic carcinogenesis.

Project description: Not available

| S-EPMC6158508 | biostudies-literature

Hepatic expression data from 2-stage carcinogenesis study in rats

Project description:Hepatic gene expression profiles in 2-stage carcinogenesis study were analyzed with comprehensive DNA methylation data. Combined analysis suggested that PTEN signaling and immune response such as antigen presentation was related to one side of early heapatocarcinogenesis. We used microarrays to obtain the global gene expression profile of livers to understand the mechanism of carcinogenesis.

2016-10-24 | GSE51797 | GEO

Transcription profiling of rodent hepatic carcinogenesis

Project description:3 dose levels of each of 9 compounds were used to dose male SD rats q.d. by oral gavage. Compounds included 5 nongenotoxic carcinogens (bemitradine, clofibrate, doxylamine, methapyrilene, & phenobarbital), 2 genotoxic agents (tamoxifen and 2-AAF) and 2 non-carcinogens (4-AAF and isoniazid). This work has been described in Kramer JA, Curtiss SW, Kolaja KL, Alden CA, Blomme EAG, Curtiss WC, Davila JC, Jackson CJ, and Bunch RT. (2004) Acute Molecular Markers of Rodent Hepatic Carcinogenesis Identified by Transcription Profiling. Chem. Res. Toxicol., in press.

2004-03-08 | E-MEXP-89 | biostudies-arrayexpress

Epigenetic reprogramming shapes the cellular landscape of schwannoma

Project description:Cell state evolution underlies tumor development and response to therapy1, but mechanisms specifying cancer cell states and intratumor heterogeneity are incompletely understood. Schwannomas are the most common tumors of the peripheral nervous system and are treated with surgery and ionizing radiation2–5. Schwannomas can oscillate in size for many years after radiotherapy6,7, suggesting treatment may reprogram schwannoma cells or the tumor microenvironment. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas. We find schwannomas are comprised of 2 molecular groups distinguished by reactivation of neural crest development pathways or misactivation of nerve injury mechanisms that specify cancer cell states and the architecture of the tumor immune microenvironment. Schwannoma molecular groups can arise independently, but ionizing radiation is sufficient for epigenetic reprogramming of neural crest to immune-enriched schwannoma by remodeling chromatin accessibility, gene expression, and metabolism to drive schwannoma cell state evolution and immune cell infiltration. To define functional genomic mechanisms underlying epigenetic reprograming of schwannomas, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of cancer evolution and establish a paradigm of epigenetic reprograming of cancer in response to radiotherapy.

2023-04-18 | PXD014798 | Pride

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