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Epigenetic downregulation of TET3 reduces genome‐wide 5hmC levels and promotes glioblastoma tumorigenesis
Author(s) -
Carella Antonella,
Tejedor Juan R.,
García María G.,
Urdinguio Rocío G.,
Bayón Gustavo F.,
Sierra Marta,
López Virginia,
GarcíaToraño Estela,
SantamarinaOjeda Pablo,
Pérez Raúl F.,
Bigot Timothée,
Mangas Cristina,
CorteTorres María D.,
SáenzdeSantaMaría Inés,
Mollejo Manuela,
Meléndez Bárbara,
Astudillo Aurora,
Chiara María D.,
Fernández Agustín F.,
Fraga Mario F.
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32520
Subject(s) - epigenetics , 5 hydroxymethylcytosine , carcinogenesis , dna methylation , biology , glioma , dna demethylation , histone , cancer research , gene , genetics , microbiology and biotechnology , gene expression
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.