Telomerase reverse transcriptase (TERT) ‐ enhancer of zeste homolog 2 (EZH2) network regulates lipid metabolism and DNA damage responses in glioblastoma

Abstract Elevated expression of enhancer of zeste homolog 2 ( EZH 2), a histone H3K27 methyltransferase, was observed in gliomas harboring telomerase reverse transcriptase ( TERT ) promoter mutations. Given the known involvement of TERT and EZH 2 in glioma progression, the correlation between the two and subsequently its involvement in metabolic programming was investigated. Inhibition of human telomerase reverse transcriptase either pharmacologically or through genetic manipulation not only decreased EZH 2 expression, but also (i) abrogated FASN levels, (ii) decreased de novo fatty acid accumulation, and (iii) increased ataxia‐telangiectasia‐mutated ( ATM ) phosphorylation levels. Conversely, diminished TERT and FASN levels upon si RNA ‐mediated EZH 2 knockdown indicated a positive correlation between TERT and EZH 2. Interestingly, ATM kinase inhibitor rescued TERT inhibition‐mediated decrease in FASN and EZH 2 levels. Importantly, TERT promoter mutant tumors exhibited greater microsatellite instability, heightened FASN levels and lipid accumulation. Coherent with in vitro findings, pharmacological inhibition of TERT by costunolide decreased lipid accumulation and elevated ATM expression in heterotypic xenograft glioma mouse model. By bringing TERT ‐ EZH 2 network at the forefront as driver of dysregulated metabolism, our findings highlight the non‐canonical but distinct role of TERT in metabolic reprogramming and DNA damage responses in glioblastoma. image