Cell reports. Medicine · 2025
Targeting TET3 suppresses group 3 medulloblastoma stemness and progression via impairing hypomethylation of Otx2 super-enhancer.
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Chen Xuan, Wang Ziwei, Song Yan, Su Yu, Zhao Yahui, Li Jiankang, Wang Wei, Zhang Jiao, Daniels Craig, Wu Xiaochong, Saulnier Olivier, Wang Yanan, Liu Fei, Deng Kaiwen, Han Dongming, Liu Zijia, Li Meiyu, Hendrikse Liam D, Rasnitsyn Alexandra, Wang Evan Y, Wang Dongyang, Feng Zhaoyang, Li Yanong, Zhao Zitong, Yuan Hongyu, Sun Youliang, Jiang Yifei, Shi Yanfeng, Yang Tao, Qi Xueling, Hou Yong, Li Chunde, Liu Yong-Qiang, Tian Yu, Li Shuaicheng, Qiu Xiaoguang, Taylor Michael D, Li Guo Liang, Jiang Tao, Liu Hailong
Аннотация
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.