Do gliomas originate in epigenomic alterations?
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Do gliomas originate in epigenomic alterations?
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Do gliomas originate in epigenomic alterations?
Although cancer is generally considered a genetic disease driven by somatic mutations, epigenetic alterations in cancer are very common.
Glioma, leukemia, and colorectal cancer frequently exhibit a “methylated phenotype” characterized by hypermethylation of CpG islands and other CpG-rich sequence elements.
Excessive DNA methylation has been shown to silence the promoters of tumor suppressor genes, it can also damage non-coding regulatory elements called “insulators”, resulting in aberrant enhancer-promoter interactions, which have the potential to induce oncogenes potential.
A veritable epigenetic mark, DNA methylation is inherited through cell division, yet epigenetic variability in most tumors prevents us from distinguishing whether it acts as a driver of cancer or simply as an accompanying event . Furthermore, we currently lack in vitro and in vivo experimental models to validate and functionally characterize potential driver epigenetic lesions.
On July 25, 2023, researchers from Dana-Farber Cancer Institute published a research paper entitled: Modeling epigenetic lesions that cause gliomas in the academic journal Cell .
While cancer often arises from mutations and other changes in the DNA of cells, this latest study found that gliomas arise from changes in the epigenome.
These findings highlight the therapeutic potential of suppressing glioma by targeting the epigenome.
Gliomas can be driven by epigenetic changes, suggesting that new chemotherapy drugs that target these changes may hold the key to stopping brain tumor growth.
Tumors with mutations in isocitrate dehydrogenase (IDH) , including low-grade gliomas and certain leukemias, exhibit severe DNA hypermethylation.
Mutated IDH produces a new form of enzymatic activity that produces high levels of 2-hydroxyglutarate (2HG) , an inhibitor of DNA demethylases. In IDH-mutated gliomas, hypermethylation is thought to affect tumor suppressor genes, although the precise targets have not been identified.
Hypermethylation also disrupts CTCF insulators, potentially altering topologically associated domain organization and allowing aberrant activation of proto-oncogenes by enhancers.
However, despite evidence from human tumors, the ability of these epigenetic changes to enhance proliferation and/or transformation of progenitor cells has not been demonstrated.
In addition, IDH mutations also affect histone demethylases and other iron-dependent hydroxylases. Thus, the mechanisms by which IDH mutations and associated hypermethylation drive tumorigenesis remain controversial.
Although IDH-mutant glioma has a better prognosis than IDH-normal glioma, it remains incurable and ultimately fatal. Experimental models to study these low-grade tumors are woefully inadequate.
Collectively, epigenetic lesions that disrupt regulatory elements are potential cancer drivers, but we lack experimental models to validate their oncogenic roles.
In this latest study, the research team modeled the aberrations seen in isocitrate dehydrogenase (IDH) -mutant gliomas, which manifest as DNA hypermethylation.
The research team focused on the CTCF insulator near the PDGFRA oncogene, which is frequently disrupted by methylation in these tumors.
Here we demonstrate that disruption of the syntenic insulator of oligodendrocyte progenitor cells (OPCs) in mice allows OPC-specific enhancers to contact and induce Pdgfra, thereby increasing their proliferation.
The study also identified a second impairment, methylation-dependent silencing of the Cdkn2a tumor suppressor, associated with insulator loss in OPCs.
Cooperative inactivation of the Pdgfra insulator and Cdkn2a drives gliomagenesis in vivo. Although the loci are syntenic, insulators are CpG-rich only in humans, a feature that may increase glioma risk in humans but complicates mouse models.
This study demonstrates the ability of recurrent epigenetic damage to drive OPC proliferation in vitro and glioma formation in vivo.
Overall, the study identified two genes whose activity is epigenetically altered in human gliomas — the cancer-driving oncogene PDGFRA and the cancer-preventing tumor suppressor CDKN2A .
In mouse models, epigenomic alterations that activate oncogenes and silence tumor suppressor genes simultaneously stimulate glioma formation, findings that underscore the therapeutic potential of targeting the epigenome to suppress gliomas.
Gliomas can be driven by epigenetic changes, suggesting that new chemotherapy drugs that target these changes may hold the key to stopping brain tumor growth.
Paper link :
https://www.cell.com/cell/fulltext/S0092-8674(23)00729-8
Do gliomas originate in epigenomic alterations?
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