Ten-eleven translocation protein 1 modulates medulloblastoma progression

• Type of Material: Article
• Authors: H Kim, Emory Univ Sch Med; Yunhee Kang, Emory University; Yujing Li, Emory University; L Lin, Emory Univ Sch Med; L Chen, Indiana Univ Sch Med; ND Johnson, Emory Univ Sch Med; Dan Zhu, Emory University; MH Robinson, Emory Univ Sch Med; L McSwain, Emory Univ Sch Med; Benjamin Barwick, Emory University; X Yuan, Central South University; X Liao, Central South University; J Zhao, Central South University; Z Zhang, Central South University; Q Shu, Zhejiang University; J Chen, City Hope Natl Med Ctr; Emily Allen, Emory University; Anna Kenney, Emory University; Robert Castellino, Emory University; Erwin Van Meir, Emory University; Karen Conneely, Emory University; Peng Jin, Emory University; Paula Vertino, Emory University; Jian Li, Emory University
• Language: English
• Date: 2021-04-29
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s). 2021.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13059-021-02352-9
• Title of Journal or Parent Work: Genome Biology
• Volume: 22
• Issue: 1
• Start Page: 125
• End Page: 125
• Grant/Funding Information: This research was supported in part by National Institute of Health (NS079625 to PJ, CA235162 and NS096236 to EGVM), Winship Invest$ pilot grant (P30CA138292 to PJ), National Natural Science Foundation of China (No. 81902551) and the CURE Childhood Cancer Foundation (to EGVM).
• Keywords: Read alignment; Science & Technology; Biotechnology & Applied Microbiology; Medulloblastoma; 5-hydroxymethylcytosine; TET1; DNA Demethylation; 5-Methylclosine; PDGF signaling pathway; 5-Hydroxymethylcytosine; Genes; NANOG; Molecular subgroups; Transcription; Genetics & Heredity; Stem cells; Mouse models; Stem-like property; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology; Biology, Genetics; Biology, Neuroscience

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.