%0 Journal Article
%A Chen, Xuan
%A Wang, Ziwei
%A Song, Yan
%A Su, Yu
%A Zhao, Yahui
%A Li, Jiankang
%A Wang, Wei
%A Zhang, Jiao
%A Daniels, Craig
%A Wu, Xiaochong
%A Saulnier, Olivier
%A Wang, Yanan
%A Liu, Fei
%A Deng, Kaiwen
%A Han, Dongming
%A Liu, Zijia
%A Li, Meiyu
%A Hendrikse, Liam D
%A Rasnitsyn, Alexandra
%A Wang, Evan Y
%A Wang, Dongyang
%A Feng, Zhaoyang
%A Li, Yanong
%A Zhao, Zitong
%A Yuan, Hongyu
%A Sun, Youliang
%A Jiang, Yifei
%A Shi, Yanfeng
%A Yang, Tao
%A Qi, Xueling
%A Hou, Yong
%A Li, Chunde
%A Liu, Yong-Qiang
%A Tian, Yu
%A Li, Shuaicheng
%A Qiu, Xiaoguang
%A Taylor, Michael D
%A Li, Guo Liang
%A Jiang, Tao
%A Liu, Hailong
%T Targeting TET3 suppresses group 3 medulloblastoma stemness and progression via impairing hypomethylation of Otx2 super-enhancer.
%J Cell reports / Medicine
%V nn
%@ 2666-3791
%C Cambridge, MA
%I Cell Press
%M DKFZ-2025-02735
%P nn
%D 2025
%Z epub / Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
%X 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.
%K DNA hypomethylation (Other)
%K Otx2 (Other)
%K TET3 (Other)
%K medulloblastoma (Other)
%K treatment (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41338221
%R 10.1016/j.xcrm.2025.102474
%U https://inrepo02.dkfz.de/record/306751