Abstract
DNA methylation is a reversible process catalyzed by the ten–eleven translocation (TET) family of enzymes (TET1, TET2, TET3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Altered patterns of 5hmC and 5mC are widely reported in human cancers and loss of 5hmC correlates with poor prognosis. Understanding the mechanisms leading to 5hmC loss and its role in oncogenesis will advance the development of epigenetic-based therapeutics. We show that TET2 loss associates with glioblastoma (GBM) stem cells and correlates with poor survival of GBM patients. We further identify a SOX2:miR-10b-5p:TET2 axis that represses TET2 expression, represses 5hmC, increases 5mC levels, and induces GBM cell stemness and tumor-propagating potential. In vivo delivery of a miR-10b-5p inhibitor that normalizes TET2 expression and 5hmC levels inhibits tumor growth and prolongs survival of animals bearing pre-established orthotopic GBM xenografts. These findings highlight the importance of TET2 and 5hmC loss in Sox2-driven oncogenesis and their potential for therapeutic targeting.
Highlights
Cancer is as much an epigenetic disease as it is genetic and we recognize that DNA methylation, histone modification, chromatin architecture, and RNA-mediated gene regulation play fundamental roles during tumorigenesis.[1]
DNA methylation generally occurs on cytosine-guanine (CpG) sequences and is established by DNMTs, which catalyze the conversion of cytosine to 5-methylcytosine (5mC)
Our results suggest that TET2 suppresses GBM cell stemness
Summary
Cancer is as much an epigenetic disease as it is genetic and we recognize that DNA methylation, histone modification, chromatin architecture, and RNA-mediated gene regulation play fundamental roles during tumorigenesis.[1]. DNA methylation is a reversible process thought to occur spontaneously until the discovery of the ten–eleven translocation (TET) family of enzymes.[7]. These enzymes function as dioxygenases that catalyze the conversion of 5mC to 5-hydroxymethylcytosine (5hmC). Multiple studies identify reduced 5hmC levels in several cancers and correlations between the loss or inactivation of TETs with tumor progression. These associations strongly suggest that TET enzymes activate tumor suppressing mechanisms.[8,9]. The mechanisms leading to the loss of 5hmC in cancer and the role this phenomenon plays in establishing and maintaining tumor-propagating cell populations remains poorly understood These associations strongly suggest that TET enzymes activate tumor suppressing mechanisms.[8,9] the mechanisms leading to the loss of 5hmC in cancer and the role this phenomenon plays in establishing and maintaining tumor-propagating cell populations remains poorly understood
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