TY  - JOUR
AU  - Chen, Xuan
AU  - Wang, Ziwei
AU  - Song, Yan
AU  - Su, Yu
AU  - Zhao, Yahui
AU  - Li, Jiankang
AU  - Wang, Wei
AU  - Zhang, Jiao
AU  - Daniels, Craig
AU  - Wu, Xiaochong
AU  - Saulnier, Olivier
AU  - Wang, Yanan
AU  - Liu, Fei
AU  - Deng, Kaiwen
AU  - Han, Dongming
AU  - Liu, Zijia
AU  - Li, Meiyu
AU  - Hendrikse, Liam D
AU  - Rasnitsyn, Alexandra
AU  - Wang, Evan Y
AU  - Wang, Dongyang
AU  - Feng, Zhaoyang
AU  - Li, Yanong
AU  - Zhao, Zitong
AU  - Yuan, Hongyu
AU  - Sun, Youliang
AU  - Jiang, Yifei
AU  - Shi, Yanfeng
AU  - Yang, Tao
AU  - Qi, Xueling
AU  - Hou, Yong
AU  - Li, Chunde
AU  - Liu, Yong-Qiang
AU  - Tian, Yu
AU  - Li, Shuaicheng
AU  - Qiu, Xiaoguang
AU  - Taylor, Michael D
AU  - Li, Guo Liang
AU  - Jiang, Tao
AU  - Liu, Hailong
TI  - Targeting TET3 suppresses group 3 medulloblastoma stemness and progression via impairing hypomethylation of Otx2 super-enhancer.
JO  - Cell reports / Medicine
VL  - nn
SN  - 2666-3791
CY  - Cambridge, MA
PB  - Cell Press
M1  - DKFZ-2025-02735
SP  - nn
PY  - 2025
N1  - epub / Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
AB  - 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.
KW  - DNA hypomethylation (Other)
KW  - Otx2 (Other)
KW  - TET3 (Other)
KW  - medulloblastoma (Other)
KW  - treatment (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:41338221
DO  - DOI:10.1016/j.xcrm.2025.102474
UR  - https://inrepo02.dkfz.de/record/306751
ER  -