Targeting TET3 suppresses group 3 medulloblastoma stemness and progression via impairing hypomethylation of Otx2 super-enhancer

Xuan Chen; Ziwei Wang; Yan Song; Yu Su; Yahui Zhao; Jiankang Li; Wei Wang; Jiao Zhang; Craig Daniels; Xiaochong Wu; Olivier Saulnier; Yanan Wang; Fei Liu; Kaiwen Deng; Dongming Han; Zijia Liu; Meiyu Li; Liam D Hendrikse; Alexandra Rasnitsyn; Evan Y Wang; Dongyang Wang; Zhaoyang Feng; Yanong Li; Zitong Zhao; Hongyu Yuan; Youliang Sun; Yifei Jiang; Yanfeng Shi; Tao Yang; Xueling Qi; Yong Hou; Chunde Li; Yong-Qiang Liu; Yu Tian; Shuaicheng Li; Xiaoguang Qiu; Michael D Taylor; Guo Liang Li; Tao Jiang; Hailong Liu

doi:10.1016/j.xcrm.2025.102474

Targeting TET3 suppresses group 3 medulloblastoma stemness and progression via impairing hypomethylation of Otx2 super-enhancer

Cell Rep Med. 2025 Dec 16;6(12):102474. doi: 10.1016/j.xcrm.2025.102474. Epub 2025 Dec 2.

Authors

Xuan Chen¹, Ziwei Wang², Yan Song³, Yu Su⁴, Yahui Zhao⁵, Jiankang Li⁶, Wei Wang⁷, Jiao Zhang⁸, Craig Daniels⁸, Xiaochong Wu⁸, Olivier Saulnier⁹, Yanan Wang¹⁰, Fei Liu¹¹, Kaiwen Deng¹¹, Dongming Han¹, Zijia Liu¹, Meiyu Li¹, Liam D Hendrikse¹², Alexandra Rasnitsyn¹³, Evan Y Wang¹², Dongyang Wang¹⁴, Zhaoyang Feng¹¹, Yanong Li¹⁵, Zitong Zhao¹⁶, Hongyu Yuan¹⁷, Youliang Sun¹⁷, Yifei Jiang¹⁸, Yanfeng Shi¹⁹, Tao Yang²⁰, Xueling Qi²¹, Yong Hou²², Chunde Li¹⁴, Yong-Qiang Liu²³, Yu Tian²⁴, Shuaicheng Li²⁵, Xiaoguang Qiu²⁶, Michael D Taylor⁸, Guo Liang Li²⁷, Tao Jiang²⁸, Hailong Liu²⁹

Affiliations

¹ College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; BGI Research, Chongqing 401329, China; BGI Research, Shenzhen, Guangdong 518083, China.
² BGI Research, Chongqing 401329, China; BGI Research, Shenzhen, Guangdong 518083, China.
³ State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 10029, China.
⁴ School of Public Health, Capital Medical University, Beijing 100069, China.
⁵ Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Beijing Neurosurgical Institute, Beijing 100070, China.
⁶ BGI Research, Chongqing 401329, China; BGI Research, Shenzhen, Guangdong 518083, China; Computer Science Department, City University of Hong Kong, Kowloon, Hong Kong, China; State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen 518083, China.
⁷ Laboratory of Tumor Immunology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
⁸ Cancer and Hematology Center, Texas Children's Hospital, Houston, TX 77002, USA; Department of Pediatrics-Hematology/Oncology and Neurosurgery, Baylor College of Medicine, Houston, TX 77002, USA; The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1, Canada; The Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1, Canada.
⁹ Genomics and Development of Childhood Cancers Lab, Inserm U1330, Institut Curie, PSL University, SiREDO Oncology Center, Paris, France.
¹⁰ State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
¹¹ Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
¹² The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1, Canada; The Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1, Canada.
¹³ The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1, Canada; The Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1, Canada.
¹⁴ Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
¹⁵ Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
¹⁶ State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
¹⁷ Institute of Basic Medicine, School of Medicine, Tsinghua University, Beijing 100084, China.
¹⁸ University of Michigan-Shanghai Jiao Tong University Joint Institute, Shanghai Jiao Tong University, Shanghai 200240, China; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁹ China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
²⁰ China National GeneBank, BGI-Research, Shenzhen, Guangdong 518083, China.
²¹ Department of Neuro-Pathology, Sanbo Brain Hospital Capital Medical University, Beijing 100093, China.
²² College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; BGI Research, Shenzhen, Guangdong 518083, China.
²³ Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China.
²⁴ School of Public Health, Capital Medical University, Beijing 100069, China; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁵ Computer Science Department, City University of Hong Kong, Kowloon, Hong Kong, China.
²⁶ Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1, Canada.
²⁷ State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 10029, China. Electronic address: glli@buct.edu.cn.
²⁸ Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Beijing Neurosurgical Institute, Beijing 100070, China. Electronic address: zacharytaojiang@163.com.
²⁹ China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Beijing Neurosurgical Institute, Beijing 100070, China; Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Chinese Institute for Medical Research, Beijing 100069, China. Electronic address: liuhailonger@163.com.

Abstract

Medulloblastoma (MB), particularly Group_3 (G3-MB), remains the most aggressive subgroup due to strong stemness and therapeutic resistance. Through genome-wide DNA methylation and transcriptomic analysis of human MB samples, we identify enhancer hypomethylation as a key feature sustaining G3-MB stemness and tumor progression. Notably, hypomethylation of the Otx2 super-enhancer (SE) is a prognostic marker and potential therapeutic target for G3-MB patients. We demonstrate that disrupting Otx2 SE activity effectively reduces tumor growth in vivo, highlighting its critical role in G3-MB maintenance. TET3, recruited by OTX2, demethylates the Otx2 SE, promoting chromatin opening and sustaining tumor proliferation and stemness. To translate these findings into therapy, we develop a liposomal nanoparticle (LNP)-based delivery system for siTET3 or a cytosine-based inhibitor of TET3, achieving significant tumor-suppressive effect in a patient-derived orthotopic xenograft model of G3-MB. Our study provides the targeted approach for Otx2-driven G3-MB and introduces LNP-based epigenetic therapy as a promising low-toxicity strategy.

Keywords: DNA hypomethylation; Otx2; TET3; medulloblastoma; treatment.

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation
Cerebellar Neoplasms* / genetics
Cerebellar Neoplasms* / pathology
DNA Methylation* / genetics
Dioxygenases* / antagonists & inhibitors
Dioxygenases* / genetics
Dioxygenases* / metabolism
Disease Progression
Female
Gene Expression Regulation, Neoplastic
Humans
Medulloblastoma* / drug therapy
Medulloblastoma* / genetics
Medulloblastoma* / metabolism
Medulloblastoma* / pathology
Mice
Neoplastic Stem Cells* / metabolism
Neoplastic Stem Cells* / pathology
Otx Transcription Factors* / genetics
Otx Transcription Factors* / metabolism
Xenograft Model Antitumor Assays

Substances

Otx Transcription Factors
OTX2 protein, human
Dioxygenases