Ten-eleven translocation protein 1 modulates medulloblastoma progression.

Abstract

BACKGROUND:

Medulloblastoma (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.

RESULTS:

We 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 of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes.

CONCLUSIONS:

These 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.

• Authors: Hyerim Kim, Yunhee Kang, Yujing Li, Li Chen, Li Lin, Nicholas D Johnson, Dan Zhu, M Hope Robinson, Leon McSwain, Benjamin G Barwick, Xianrui Yuan, Xinbin Liao, Jie Zhao, Zhiping Zhang, Qiang Shu, Jianjun Chen, Emily G Allen, Anna M Kenney, Robert C Castellino, Erwin G Van Meir, Karen N Conneely, Paula M Vertino, Peng Jin, Jian Li
• Journal: Genome biology (Genome Biol) Vol. 22 Issue 1 Pg. 125 (04 29 2021) ISSN: 1474-760X [Electronic] England
• PMID: 33926529 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Proto-Oncogene Proteins
• 5-hydroxymethylcytosine
• 5-Methylcytosine
• Mixed Function Oxygenases
• TET1 protein, human

Topics

• 5-Methylcytosine (analogs & derivatives)
• Animals
• Biomarkers, Tumor
• Computational Biology (methods)
• CpG Islands
• DNA Methylation
• Databases, Nucleic Acid
• Disease Models, Animal
• Disease Progression
• Disease Susceptibility
• Epigenesis, Genetic
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Medulloblastoma (etiology, metabolism, mortality, pathology)
• Mice
• Mice, Transgenic
• Mixed Function Oxygenases (genetics, metabolism)
• Nucleotide Motifs
• Prognosis
• Proto-Oncogene Proteins (genetics, metabolism)