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

• Published in: International journal of cancer 2020-01, Vol.146 (2), p.373-387
• Main Authors: Carella, Antonella, Tejedor, Juan R., García, María G., Urdinguio, Rocío G., Bayón, Gustavo F., Sierra, Marta, López, Virginia, García‐Toraño, Estela, Santamarina‐Ojeda, Pablo, Pérez, Raúl F., Bigot, Timothée, Mangas, Cristina, Corte‐Torres, María D., Sáenz‐de‐Santa‐María, Inés, Mollejo, Manuela, Meléndez, Bárbara, Astudillo, Aurora, Chiara, María D., Fernández, Agustín F., Fraga, Mario F.
• Format: Article
• Language: English
• Subjects: 5-Methylcytosine - analogs & derivatives; 5-Methylcytosine - metabolism; 5‐hydroxymethylcytosine; Animal models; Animals; Biopsy; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Brain tumors; Cancer; Carcinogenesis - genetics; Cell Line, Tumor; Deoxyribonucleic acid; Dioxygenases - genetics; DNA; DNA Methylation; Down-Regulation; Epigenesis, Genetic; Epigenetics; Gene Expression Regulation, Neoplastic; Gene regulation; Genomes; Glioblastoma; Glioblastoma - genetics; Glioblastoma - mortality; Glioblastoma - pathology; Glioblastoma cells; Glioma; Glioma cells; Histone Code - genetics; Humans; Immunodeficiency; Medical research; methylation arrays; Mice; mRNA; Prognosis; RNA, Messenger - metabolism; Survival Analysis; TET3; Translocation; Tumor cell lines; Tumorigenesis; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32520

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. What's new? Reduced levels of 5‐hydroxymethylcytosine (5hmC), an epigenetic mark generated by TET enzymes, have been observed in multiple cancers. Although mutations in TET enzymes have been associated with 5hmC loss, other mechanisms may be at play. Here, the authors show that DNA hypermethylation, loss of DNA hydroxymethylation, and reduction of activating histone marks in the TET3 gene impair TET3 expression and lead to a genome‐wide reduction in 5hmC levels in glioma. Important protease inhibitor and TET3 downstream target gene RECK might help mediate tumorigenesis. The results suggest that epigenetic repression of TET3 promotes glioblastoma tumorigenesis through the genome‐wide alteration of 5hmC.