Epigenetic changes induced by TET1-mediated 5hmC production are required for glioblastomagenesis.
Major finding: Epigenetic changes induced by TET1-mediated 5hmC production are required for glioblastomagenesis.
Mechanism: 5hmC recruits the CHTOP–methylosome to methylate H4R3 and transactivate cancer-associated genes.
Impact: TET1 may represent a potential therapeutic target in glioblastoma.
In addition to mutations, epigenetic alterations have been implicated as drivers of tumorigenesis. Oxidation of methylated cytosine residues in DNA generates 5-hydroxymethylcytosine (5hmC), an intermediate of DNA demethylation that has also been shown to function as an epigenetic mark that recruits transcription factors and DNA repair machinery in a context-dependent manner, thereby regulating a number of biological processes. Generation of 5hmC is mediated by the tet methylcytosine dioxygenase (TET) family of enzymes, and alterations in TET enzymes result in downregulation of 5hmC in many tumors. Takai and colleagues investigated the contribution of 5hmC and TET1 to glioblastoma formation and found that, in contrast to other tumor types, human glioblastoma cells and patient samples exhibited elevated levels of 5hmC and TET1. Intriguingly, upregulation of 5hmC and TET1 was specific to proneural glioblastoma, but not other subtypes. TET1-induced 5hmC production was necessary for the proliferation and tumorigenicity of proneural glioblastoma cells both in vitro and in xenograft models. Mechanistically, TET1-mediated 5hmC enrichment promoted the expression of genes known to be involved in glioblastomagenesis via interaction with CHTOP [chromatin target of protein arginine methyltransferase 1 (PRMT1)] and subsequent recruitment of the methylosome, an arginine methyltransferase complex. Recruitment of the methylosome to 5hmC-enriched genes resulted in dimethylation of arginine 3 of histone H4 (H4R3) by PRMT1 and enhanced expression of EGFR, AKT3, CDK6, CCND2, and BRAF, which was diminished upon knockdown of either CHTOP or TET1. Furthermore, expression of CHTOP was required for the maintenance of elevated levels of 5hmC as well as the tumorigenicity of glioblastoma cells. In sum, these data identify 5hmC-induced transcriptional regulation as an important mediator of proneural glioblastomagenesis and suggest inhibition of TET1 as a potential therapeutic strategy in these tumors.