Oncometabolite D-2-hydroxyglutarate regulates actin dynamics and nuclear homeostasis in IDH1-mutant glioma

In gliomas harboring IDH1 mutations, accumulation of the oncometabolite D-2-hydroxyglutarate (D-2-HG) drives epigenetic dysregulation and altered signaling pathways. Though dysregulated actin cytoskeletal architecture is a hallmark of glioblastoma, the influence of glioma-associated oncometabolites on actin dynamics remains poorly understood. Genome-wide DNA methylation analysis of patient tumor biopsies stratified by IDH mutation status revealed widespread hypermethylation of actin-regulatory genes in IDH mutant gliomas. This coincided with reduced expression of key cytoskeletal proteins CFL1, CDC42 and ARP2 in IDH mutant tumors. Similar change observed in IDH1 R132H over-expressing or D-2-HG-treated glioma cells was accompanied by reduced F-actin/G-actin ratio and diminished Rho-GTPase activity, indicating reduced actin polymerization. Elevated G-actin accumulation was concomitant with reduction in lamin A and TERT levels, and increase in DNA damage marker γH2AX. Notably, lamin A functioned as a positive or negative regulator of TERT and γH2AX, respectively. Telomere FISH demonstrated changes in nuclear organization of telomeres in D-2-HG-treated cells which also exhibited altered nuclear morphology. Importantly, enforced nuclear actin polymerization in D-2-HG-treated cells restored lamin A expression, rescued diminished TERT levels, and decreased γH2AX; thereby suggesting a functional link between actin dynamics and nuclear state. Collectively, our findings uncover a previously unrecognized role for oncometabolite D-2-HG in modulating actin dynamics, and bridges the mechanistic gap between the structural-metabolic coupling mechanism in glioma.