Journal Article

DKFZ-2025-02735

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Targeting TET3 suppresses group 3 medulloblastoma stemness and progression via impairing hypomethylation of Otx2 super-enhancer.

Chen, X. ; Wang, Z. ; Song, Y. ; Su, Y. ; Zhao, Y. ; Li, J. ; Wang, W. ; Zhang, J. ; Daniels, C. ; Wu, X. ; Saulnier, O. ; Wang, Y. ; Liu, F. ; Deng, K. ; Han, D. ; Liu, Z. ; Li, M. ; Hendrikse, L. D. ; Rasnitsyn, A. ; Wang, E. Y. ; Wang, D. ; Feng, Z. ; Li, Y. ; Zhao, Z. ; Yuan, H. ; Sun, Y. ; Jiang, Y. ; Shi, Y. ; Yang, T. ; Qi, X. ; Hou, Y. ; Li, C. ; Liu, Y.-Q. ; Tian, Y.DKFZ* ; Li, S. ; Qiu, X. ; Taylor, M. D. ; Li, G. L. ; Jiang, T. ; Liu, H.

2025
Cell Press Cambridge, MA

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.

Keyword(s): DNA hypomethylation ; Otx2 ; TET3 ; medulloblastoma ; treatment

Note: epub / Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

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Contributing Institute(s):

1. Epidemiologie von Krebs (C020)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2025

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