Targeting TET3 suppresses group 3 medulloblastoma stemness and progression via impairing hypomethylation of Otx2 super-enhancer
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.
Authors
- Yu Tian (ORCID: https://orcid.org/0000-0001-7218-5954)
- Wei Wang (ORCID: https://orcid.org/0000-0001-8388-0987)
- Evan Y. Wang (ORCID: https://orcid.org/0000-0001-7984-3147)
- Yanong Li (ORCID: https://orcid.org/0000-0001-8121-3777)
- Dongyang Wang (ORCID: https://orcid.org/0009-0007-4629-2829)
- Jiankang Li (ORCID: https://orcid.org/0000-0002-5061-4460)
- Olivier Saulnier (ORCID: https://orcid.org/0000-0003-4111-1017)
- Yan Song (ORCID: https://orcid.org/0000-0003-2215-1101)
- Yifei Jiang (ORCID: https://orcid.org/0000-0003-1941-7116)
- Dongming Han (ORCID: https://orcid.org/0009-0006-5622-2042)
- Xiaoguang Qiu (ORCID: https://orcid.org/0000-0002-6806-9827)
- Yong Hou (ORCID: https://orcid.org/0000-0002-0420-0726)
- Zijia Liu (ORCID: https://orcid.org/0000-0002-1866-4337)
- Tao Jiang (ORCID: https://orcid.org/0000-0002-7008-6351)
- Chunde Li (ORCID: https://orcid.org/0000-0001-8443-8613)
- Yu Su (ORCID: https://orcid.org/0000-0001-7807-5107)
- Shuai Cheng Li (ORCID: https://orcid.org/0000-0001-6246-6349)
- Kaiwen Deng (ORCID: https://orcid.org/0009-0002-9517-2851)
- Alexandra Rasnitsyn
- Jiao Zhang (ORCID: https://orcid.org/0000-0002-9106-2156)
- Yanan Wang (ORCID: https://orcid.org/0000-0002-8050-3155)
- Ziwei Wang (ORCID: https://orcid.org/0000-0003-4135-3024)
- Guoliang Li (ORCID: https://orcid.org/0000-0003-1601-6640)
- Xuan Chen (ORCID: https://orcid.org/0000-0001-5553-3638)
- Michael D. Taylor (ORCID: https://orcid.org/0000-0001-7009-3466)
- Yongqiang Liu (ORCID: https://orcid.org/0000-0003-3826-6878)
- Tao Yang (ORCID: https://orcid.org/0000-0002-3691-3819)
- Hongyu Yuan
- Meiyu Li (ORCID: https://orcid.org/0009-0005-4065-2104)
- Yanfeng Shi (ORCID: https://orcid.org/0000-0002-6176-7307)
- Zitong Zhao (ORCID: https://orcid.org/0000-0001-9279-0924)
- Youliang Sun
- Hailong Liu (ORCID: https://orcid.org/0000-0002-4983-8555)
- Xueling Qi (ORCID: https://orcid.org/0000-0002-8483-8382)
- Zhaoyang Feng
- Liam D. Hendrikse
- Craig Daniels
- Yahui Zhao
- Xiaochong Wu
- Fei Liu (ORCID: https://orcid.org/0009-0005-0576-440X)
Institutions
- BGI Group (China) (CN)
- Guangzhou University of Chinese Medicine (CN)
- Inserm (FR)
- City University of Hong Kong (HK)
- German Cancer Research Center (DE)
- Shanghai Jiao Tong University (CN)
- Capital Medical University (CN)
- University of Toronto (CA)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Heidelberg University (DE)
- Université Paris Sciences et Lettres (FR)
- Hospital for Sick Children (CA)
- Beijing Tian Tan Hospital (CN)
- Beijing Sanbo Brain Hospital (CN)
- Beijing Institute of Neurosurgery (CN)
- Beijing Children’s Hospital (CN)
- China National GeneBank (CN)
- University of Chinese Academy of Sciences (CN)
- Beijing University of Chemical Technology (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102474
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00