Epigenetic downregulation of TET3 reduces genome‐wide 5hmC levels and promotes glioblastoma tumorigenesis

Abstract

Loss of 5‐hydroxymethylcytosine (5hmC) has been associated with mutations of the ten–eleven translocation (TET) enzymes in several types of cancer. However, tumors with wild‐type TET genes can also display low 5hmC levels, suggesting that other mechanisms involved in gene regulation might be implicated in the decline of this epigenetic mark. Here we show that DNA hypermethylation and loss of DNA hydroxymethylation, as well as a marked reduction of activating histone marks in the TET3 gene, impair TET3 expression and lead to a genome‐wide reduction in 5hmC levels in glioma samples and cancer cell lines. Epigenetic drugs increased expression of TET3 in glioblastoma cells and ectopic overexpression of TET3 impaired in vitro cell growth and markedly reduced tumor formation in immunodeficient mice models. TET3 overexpression partially restored the genome‐wide patterns of 5hmC characteristic of control brain samples in glioblastoma cell lines, while elevated TET3 mRNA levels were correlated with better prognosis in glioma samples. Our results suggest that epigenetic repression of TET3 might promote glioblastoma tumorigenesis through the genome‐wide alteration of 5hmC.

Values of 5mC, 5hmC, and TET2 for identifying the presence and progression of breast precancerous lesion

“…Considering that 5mC and TET2 are both closely related to the regulation of DNA methylation, it might be reasonable to hypothesize that 5mC and TET2 also participate in the etiology of the existence or progression of precancerous lesion. In this study, we found that 5hmC and TET2 expressions were both negatively correlated with the histological classification, and here were several possible explanations to the results in our study: (a) 5hmC and TET2 might prevent the formation or repress the progression of breast precancerous lesion via modulating stemness or other related processes, which still need more in vivo and in vitro experiments to validate; (b) 5hmC and TET2 might also inhibit precancerous lesion development and progression via similar mechanism by which they suppress the cancer progression, for instance, repressing malignant behaviors of cancer cells by mediating multiple oncogenic signaling pathways . However, we did not find a statistically significant correlation between 5mC and histopathological classification, which may be due to the dual role of 5mC in cancer pathogenesis found in other cancers, or a relatively small sample size …”

“…These findings indicate a dual role of 5mC in tumorigenesis. As for 5hmC, a previous study reveals that epigenetically reduction of TET3 expression decreases the 5hmC expression in both tumor tissue and cancer cells, and this process subsequently advocates the tumor progression of glioblastoma in vitro . And another study illustrates that restoring the 5hmC using ascorbate represses the tumor growth of clear‐cell renal cell carcinoma in vitro .…”

TET2 suppresses nasopharyngeal carcinoma progression by inhibiting glycolysis metabolism

“…TET protein family are usually considered as tumor suppressors by promoting locus-specific reversal of DNA methylation [ 13 , 28 , 29 ], however, the detailed molecular mechanisms of TET protein family regulating NPC progress are still unclear. In this study, we first examined the mRNA expression levels of TET family genes in NPC cell lines.…”

The Emerging Roles of RNA Modifications in Glioblastoma

“…For example, hm 5 C is distributed at lncRNA loci, involved in long-range chromatin interactions and positively correlated with lncRNA transcription [130]. TET1 is elevated in GBM [85], while TET2 expression is downregulated in glioma [86], and TET3 is epigenetically repressed in glioma [87]. 5-hydroxymethylcytidine in DNA has been recognized as important markers in GBM [131][132][133], however, the direct evidence of hm 5 C modification in RNA has never been explored in GBM (Figure 2, hm 5 C part).…”