Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation

Abstract

The TET (ten–eleven translocation) family of α-ketoglutarate (α-KG)-dependent dioxygenases catalyzes the sequential oxidation of 5-methylcytosine (5mC) to 5-hydroxymethyl-cytosine (5hmC), 5-formylcytosine and 5-carboxylcytosine, leading to eventual DNA demethylation. The TET2 gene is a bona fide tumor suppressor frequently mutated in leukemia, and TET enzyme activity is inhibited in IDH1/2-mutated tumors by the oncometabolite 2-hydroxyglutarate, an antagonist of α-KG, linking 5mC oxidation to cancer development. We report here that the levels of 5hmC are dramatically reduced in human breast, liver, lung, pancreatic and prostate cancers when compared with the matched surrounding normal tissues. Associated with the 5hmC decrease is the substantial reduction of the expression of all three TET genes, revealing a possible mechanism for the reduced 5hmC in cancer cells. The decrease of 5hmC was also observed during tumor development in different genetically engineered mouse models. Together, our results identify 5hmC as a biomarker whose decrease is broadly and tightly associated with tumor development.

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

“…5-Hydroxymethylation of cytosine bases (5-hmC) is a newly identified epigenetic marker; this nontraditional DNA modification involves methylation of cytosine bases (5-mC) in CpG dinucleotide sequences 2,3 and their oxidation by the ten-eleven translocation (TET) family of proteins. While 5-hmC is a potentially useful indicator of disease states such as cancer [4][5][6][7][8] , the mechanisms controlling its abundance in tumours and its impact on gene expression and cancer cell fate are unclear.…”

Epigenetic regulation mechanisms of microRNA expression

“…However, like 5mC alterations, the 5hmC patterns undergo considerable changes linked to genome instability (70,71) across several forms of human cancers (72). Recent studies revealed that 5hmC is consistently found at significantly reduced levels (more than 50% reduction, p ≤ 0.01) in various solid tumors (73)(74)(75). Recently, using a mouse model, Pan et al (76) studied the role of hydroxymethylation in neurophysiological processes and provided the first evidence that miRNAs can be regulated by hydroxymethylation of their promoters.…”

Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

“…27 TET proteins are thought to have a role in tumor development, as inhibition of TET activity, as well as alteration of global DNA methylation, has been demonstrated in multiple tumor types. [28][29][30][31][32] Thus, succinate accumulation in the context of SDH deficiency could potentially drive tumorigenesis via the inhibition of TET family proteins and subsequent changes in DNA methylation and gene expression patterns. Indeed, recent work has shown that siRNA-mediated knockdown of SDHA in cultured cells and in mice leads to an inhibition of TET activity and decreased levels of 5-hmC.…”