TET2-Driven Demethylation of ANG promotes Angiogenesis and Malignant transformation in Oligodendroglioma

Oligodendrogliomas (OG) are indolent yet inevitably progressive gliomas in which angiogenesis is tightly linked to malignant transformation, but the underlying epigenetic mechanisms remain unclear. By integrating public datasets of primary and malignant transformed OG specimens, patient-derived cell lines and orthotopic xenograft models, we identify angiogenin (ANG) as a key pro-angiogenic driver whose high expression correlates with increased microvessel density, enhanced proliferation and poor overall survival. Promoter methylation analyses reveal that ANG is heavily methylated in low-grade tumors and that hypomethylation of three CpG-rich regions including the prognostic site e.g., cg10850001, associates with increased ANG expression, higher tumor grade and worse outcome. Functional studies show that ANG knockdown suppresses VEGFA and Ki67 expression, reduces endothelial tube formation and intratumoral microvessel density, and significantly prolongs survival in Oligodendroglioma PDOX mice, whereas pharmacologic demethylation with decitabine decreases ANG promoter methylation, upregulates ANG and accelerates malignant phenotypes. Among TET dioxygenases, TET2 is selectively upregulated in malignant oligodendroglioma, directly binds to the ANG promoter, and enhances its activity; TET2 depletion increases ANG promoter methylation, downregulates ANG and pro-angiogenic markers, and impairs angiogenesis, effects that are rescued by ANG re-expression. The cell-permeable itaconate derivative 4-octyl itaconate (OI), a pharmacologic TET2 inhibitor, restores ANG promoter methylation, suppresses TET2–ANG signaling and cooperates with Temozolomide (TMZ) to inhibit tumor growth and extend survival in PDOX models. These findings define a TET2–ANG–angiogenesis axis that drives malignant transformation of oligodendroglioma and highlight itaconate-based epigenetic targeting of TET2 as a promising strategy to improve outcomes in patients with oligodendroglioma.