@article{ajmsm20261422,
author={{K., Hafkenscheid and B., Jacuinde and A., Mari and A., Gomez and C., Philip and P., Jay and AJ., Diaz and T., Wang},
title={A Bimodal Model of Temozolomide-mediated LSD1 Activity in Glioma Cells},
journal={American Journal of Medical Sciences and Medicine},
volume={14},
number={2},
pages={25--31},
year={2026},
url={https://pubs.sciepub.com/ajmsm/14/2/2},
issn={2327-6657},
abstract={Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults, with a median survival of approximately 14¨C16 months despite standard treatment. Temozolomide (TMZ) is the frontline chemotherapeutic agent for GBM and is well established as a DNA alkylating agent. However, the potential for TMZ to exert antitumor effects through direct protein-level methylation - particularly through modulation of epigenetic regulatory enzymes - has not been fully characterized. Our previous study has shown that TMZ can methylate recombinant histone H3 and alter histone methylation levels in glioma cells. Building on those findings, the present study examined whether the histone methylation changes observed after TMZ treatment in glioma cells are mediated by lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic eraser enzyme known to be overexpressed in glioma. Our results showed that TMZ suppresses LSD1 demethylase activity in a concentration-dependent fashion, consistent with a bimodal model of inhibition that becomes operative only at higher drug concentrations (¡Ý150 ¦ÌM). At lower TMZ concentrations (0¨C100 ¦ÌM), LSD1 demethylase activity remained largely unaffected, whereas significant suppression occurred at higher concentrations (150¨C200 ¦ÌM). Co-treatment with tranylcypromine (TCP) confirmed effective LSD1 inhibition at lower TMZ concentrations; however, TCP's inhibitory effectiveness diminished at higher TMZ concentrations, suggesting TMZ-induced conformational changes in LSD1 that may reduce the enzyme¡¯s accessibility to TCP binding. These findings establish that TMZ functions as a direct histone methylating regulator and suppresses LSD1 demethylase activity in a concentration-dependent manner through both indirect and direct enzyme-level mechanisms. This dual epigenetic activity expands the known pharmacological profile of TMZ and carries meaningful implications for understanding how the drug exerts its downstream effects on chromatin structure and gene expression. These results also inform the growing effort to harness epigenetic mechanisms as therapeutic targets in glioma.},
doi={10.12691/ajmsm-14-2-2}
publisher={Science and Education Publishing}
}