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

Sep 29, 2026

Uploaded by Theodore

Medulloblastoma Group 3 (G3-MB) remains highly aggressive, with strong stemness features and therapeutic resistance. By integrating genome-wide DNA methylation and transcriptomic profiling of human samples, the study identifies enhancer hypomethylation as a driver of G3-MB maintenance and progression. Hypomethylation of the Otx2 super-enhancer acts as a prognostic marker and therapeutic vulnerability. Disrupting Otx2 super-enhancer activity reduces tumor growth in vivo. TET3, recruited by OTX2, demethylates the Otx2 super-enhancer to promote chromatin opening, proliferation, and stemness. Therapeutic translation is achieved using liposomal nanoparticle delivery of siTET3 or a cytosine-based TET3 inhibitor, producing marked tumor suppression in a patient-derived orthotopic xenograft model.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages26

Reading Time1 h 6 min

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Summary

Therapeutic vulnerability via Otx2 super-enhancer hypomethylation

LNP-delivered TET3 inhibition for G3-MB suppression

Summary

Introduction

Medulloblastoma subgroups and prognosis

Summary

Therapeutic strategy

Article Targeting TET3 suppresses group 3 medulloblastoma stemness and progression via impairing hypomethylation of Otx2 super-enhancer Authors Xuan Chen, Ziwei Wang, Yan Song, ..., Guo Liang Li, Tao Jiang, Hailong Liu Correspondence [glli@buct.edu.cn](glli@buct.edu.cn) (G.L.L.), [zacharytaojiang@163.com](zacharytaojiang@163.com) (T.J.), [liuhailonger@163.com](liuhailonger@163.com) (H.L.) In brief Chen et al. identify TET3-mediated hypomethylation of the Otx2 superenhancer as a critical driver of G3-MB. Disrupting this axis with LNP-delivered siTET3 effectively suppresses tumor growth, establishing both a mechanistic hallmark and therapeutic vulnerability of G3-MB. • TET3-mediated demethylation of Otx2 super-enhancer reveals therapeutic vulnerability • LNP delivery of TET3 inhibitors or siRNAs effectively suppresses G3-MB growth Chen et al., 2025, Cell Reports Medicine 6, 102474 December 16, 2025 © 2025 The Authors. Published by Elsevier Inc. [https://doi.org/10.1016/j.xcrm.2025.102474](https://doi.org/10.1016/j.xcrm.2025.102474) ll ll OPEN ACCESS Article Targeting TET3 suppresses group 3 medulloblastoma stemness and progression via impairing hypomethylation of Otx2 super-enhancer Xuan Chen,1,2,3,29 Ziwei Wang,2,3,29 Yan Song,4,29 Yu Su,5,29 Yahui Zhao,6,7,8,29 Jiankang Li,2,3,26,27,29 Wei Wang,9 Jiao Zhang,10,11,12,13 Craig Daniels,10,11,12,13 Xiaochong Wu,10,11,12,13 Olivier Saulnier,14 Yanan Wang,15 Fei Liu,6,16 Kaiwen Deng,6,16 Dongming Han,1,2,3 Zijia Liu,1,2,3 Meiyu Li,1,2,3 Liam D. Hendrikse,12,13 (Author list continued on next page) 1College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China 2BGI Research, Chongqing 401329, China 3BGI Research, Shenzhen, Guangdong 518083, China 4State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 10029, China 5School of Public Health, Capital Medical University, Beijing 100069, China 6Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China 7China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China 8Beijing Neurosurgical Institute, Beijing 100070, China 9Laboratory of Tumor Immunology, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China 10Cancer and Hematology Center, Texas Children’s Hospital, Houston, TX 77002, USA 11Department of Pediatrics–Hematology/Oncology and Neurosurgery, Baylor College of Medicine, Houston, TX 77002, USA 12The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1, Canada 13The Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1, Canada 14Genomics and Development of Childhood Cancers Lab, Inserm U1330, Institut Curie, PSL University, SiREDO Oncology Center, Paris, France 15State 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 16Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China 17Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1, Canada (Affiliations continued on next page) SUMMARY 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 thera

FAQs

What role does TET3 play in Group 3 medulloblastoma (G3-MB)?

The study shows that TET3 is recruited by OTX2 and demethylates the Otx2 super-enhancer, promoting chromatin opening, tumor proliferation, and stemness in G3-MB.

Why is the Otx2 super-enhancer hypomethylation important?

Hypomethylation of the Otx2 super-enhancer is identified as a prognostic marker and a potential therapeutic target, sustaining G3-MB stemness and progression.

How does the study translate these findings into therapy?

It develops a liposomal nanoparticle delivery approach for siTET3 or a cytosine-based inhibitor of TET3, achieving significant tumor-suppressive effects in a patient-derived orthotopic xenograft model.

Sep 29, 2026

Uploaded by Theodore