1. Ten-eleven translocation protein 1 modulates medulloblastoma progression
- Author
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Erwin G. Van Meir, Jian Li, Qiang Shu, Karen N. Conneely, Emily G. Allen, Dan Zhu, Yunhee Kang, Li Chen, Jie Zhao, Robert C. Castellino, Li Lin, Yujing Li, M. Hope Robinson, Peng Jin, Leon F. McSwain, Benjamin G. Barwick, Paula M. Vertino, Anna Kenney, Zhiping Zhang, Jianjun Chen, Xianrui Yuan, Nicholas D. Johnson, Xinbin Liao, and Hyerim Kim
- Subjects
QH301-705.5 ,Somatic cell ,Mice, Transgenic ,Chromosomal translocation ,QH426-470 ,Biology ,medicine.disease_cause ,Epigenesis, Genetic ,Mixed Function Oxygenases ,Mice ,chemistry.chemical_compound ,Proto-Oncogene Proteins ,Biomarkers, Tumor ,Genetics ,medicine ,Animals ,Humans ,5-hydroxymethylcytosine ,Epigenetics ,Nucleotide Motifs ,Biology (General) ,Gene ,5-Hydroxymethylcytosine ,Medulloblastoma ,PDGF signaling pathway ,Gene Expression Profiling ,Research ,Stem-like property ,Computational Biology ,DNA Methylation ,Prognosis ,medicine.disease ,TET1 ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,NANOG ,chemistry ,5-Methylcytosine ,Disease Progression ,Cancer research ,CpG Islands ,Disease Susceptibility ,Databases, Nucleic Acid ,Smoothened ,Carcinogenesis - Abstract
BackgroundMedulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes.ResultsWe investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout ofTet1in the smoothened (SmoA1)mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacologicalTet1inhibition reduces cell viability andplatelet-derived growth factorsignaling pathway-associated genes.ConclusionsThese results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs.
- Published
- 2021