Ahmad Fahim, Patrick Shruti, Sheikh Touseef, Sharma Vikas, Pathak Pankaj, Malgulwar Prit Benny, Kumar Anupam, Joshi Shanker Datt, Sarkar Chitra, Sen Ellora
Division of Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar, India.
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
J Neurochem. 2017 Dec;143(6):671-683. doi: 10.1111/jnc.14152. Epub 2017 Sep 22.
Elevated expression of enhancer of zeste homolog 2 (EZH2), a histone H3K27 methyltransferase, was observed in gliomas harboring telomerase reverse transcriptase (TERT) promoter mutations. Given the known involvement of TERT and EZH2 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 EZH2 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 siRNA-mediated EZH2 knockdown indicated a positive correlation between TERT and EZH2. Interestingly, ATM kinase inhibitor rescued TERT inhibition-mediated decrease in FASN and EZH2 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-EZH2 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.
在携带端粒酶逆转录酶（TERT）启动子突变的神经胶质瘤中，观察到组蛋白H3K27甲基转移酶zeste同源物2（EZH2）的表达升高。鉴于已知TERT和EZH2参与神经胶质瘤进展，研究了两者之间的相关性及其随后在代谢编程中的作用。通过药理学方法或基因操作抑制人类端粒酶逆转录酶，不仅降低了EZH2的表达，而且（i）消除了脂肪酸合酶（FASN）水平，（ii）减少了从头脂肪酸积累，以及（iii）增加了共济失调毛细血管扩张症突变基因（ATM）的磷酸化水平。相反，在小干扰RNA介导的EZH2敲低后TERT和FASN水平降低，表明TERT与EZH2之间呈正相关。有趣的是，ATM激酶抑制剂挽救了TERT抑制介导的FASN和EZH2水平降低。重要的是，TERT启动子突变肿瘤表现出更大的微卫星不稳定性、更高的FASN水平和脂质积累。与体外研究结果一致，在异种移植神经胶质瘤小鼠模型中，木香内酯对TERT的药理学抑制降低了脂质积累并提高了ATM表达。通过将TERT-EZH2网络作为代谢失调的驱动因素置于前沿，我们的研究结果突出了TERT在胶质母细胞瘤代谢重编程和DNA损伤反应中的非经典但独特的作用。
