A Bimodal Model of Temozolomide-mediated LSD1 Activity in Glioma Cells

Hafkenscheid K.¹, Jacuinde B.¹, Mari A.¹, Gomez A.¹, Philip C.¹, Jay P.², Diaz AJ.² and Wang T.^{2, 1,}

¹Department of Clinical Science California State University Dominguez Hills, Carson, CA, USA

²Department of Chemistry and Biochemistry

Cite this paper:
Hafkenscheid K., Jacuinde B., Mari A., Gomez A., Philip C., Jay P., Diaz AJ. and Wang T.. A Bimodal Model of Temozolomide-mediated LSD1 Activity in Glioma Cells. American Journal of Medical Sciences and Medicine. 2026; 14(2):25-31. doi: 10.12691/ajmsm-14-2-2

Abstract

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults, with a median survival of approximately 14–16 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 (≥150 µM). At lower TMZ concentrations (0–100 µM), LSD1 demethylase activity remained largely unaffected, whereas significant suppression occurred at higher concentrations (150–200 µM). 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.

Keywords:
Temozolomide glioma LSD1/KDM1A histone methylation histone lysine demethylase therapeutic benefit chromatin remodeling epigenetic regulation tranylcypromine

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