Ten-eleven translocation protein 1 modulates medulloblastoma progression

Genome Biology

Li Chen¹  Benjamin G. Barwick²  Paula M. Vertino²  Li Lin³  Emily G. Allen³  Hyerim Kim³  Peng Jin³  Nicholas D. Johnson³  Yujing Li³  Yunhee Kang³  Karen N. Conneely³  Jian Li⁴  Xianrui Yuan⁵  Zhiping Zhang⁶  Xinbin Liao⁶  Jie Zhao⁶  M. Hope Robinson⁷  Leon McSwain⁷  Robert C. Castellino⁸  Anna M. Kenney⁹  Jianjun Chen^1,10  Dan Zhu^1,11  Erwin G. Van Meir^1,12  Qiang Shu^1,13 

[1] Department of Biostatistics and Health Data Science, Indiana University School of Medicine, 46202, Indianapolis, IN, USA;Department of Hematology and Medical Oncology, Emory University School of Medicine, 30322, Atlanta, GA, USA;Winship Cancer Institute, Emory University, 30322, Atlanta, GA, USA;Department of Human Genetics, Emory University School of Medicine, 30322, Atlanta, GA, USA;Department of Human Genetics, Emory University School of Medicine, 30322, Atlanta, GA, USA;Department of Neurosurgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;Hydrocephalus Center, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;Department of Neurosurgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;Department of Neurosurgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;Hydrocephalus Center, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;Department of Pediatric Oncology, Emory University School of Medicine, 30322, Atlanta, GA, USA;Department of Pediatric Oncology, Emory University School of Medicine, 30322, Atlanta, GA, USA;Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, 30322, Atlanta, GA, USA;Department of Pediatric Oncology, Emory University School of Medicine, 30322, Atlanta, GA, USA;Winship Cancer Institute, Emory University, 30322, Atlanta, GA, USA;Department of Systems Biology and Gehr Family Center for Leukemia Research, City of Hope, 91010, Duarte, CA, USA;Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University School of Medicine, 30322, Atlanta, GA, USA;Department of Hematology and Medical Oncology, Emory University School of Medicine, 30322, Atlanta, GA, USA;Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University School of Medicine, 30322, Atlanta, GA, USA;Department of Hematology and Medical Oncology, Emory University School of Medicine, 30322, Atlanta, GA, USA;Winship Cancer Institute, Emory University, 30322, Atlanta, GA, USA;The Children’s Hospital and Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China;

关键词: Medulloblastoma;    5-hydroxymethylcytosine;    TET1;    Stem-like property;    NANOG;    PDGF signaling pathway;   

DOI  :  10.1186/s13059-021-02352-9

来源: Springer

【 摘 要 】

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 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.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.

【 授权许可】

CC BY