Language
English
Publication Date
12-2-2025
Journal
Cell Reports Medicine
DOI
10.1016/j.xcrm.2025.102474
PMID
41338221
Abstract
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.
Keywords
DNA hypomethylation. Otx2. TET3. medulloblastoma. treatment
Published Open-Access
yes
Recommended Citation
Chen, Xuan; Wang, Ziwei; Song, Yan; et al., "Targeting TET3 Suppresses Group 3 Medulloblastoma Stemness and Progression via Impairing Hypomethylation of Otx2 Super-Enhancer" (2025). Faculty and Staff Publications. 5390.
https://digitalcommons.library.tmc.edu/baylor_docs/5390