Methionine concentration regulates LSD1 acetylation in glioma cells.

Glioma is a highly aggressive brain cancer with poor prognosis, characterized by vigorous methionine metabolism. While methionine restriction demonstrates broad anticancer effects, its mechanistic relationship with epigenetic regulators in glioma remains inadequately understood. This study reveals the molecular mechanism by which methionine restriction (0.1 mM) modulates the epigenetic regulator LSD1. Restricting methionine to 0.1 mM induced site-specific acetylation at LSD1 lysine residues K6 and K359, promoting its ubiquitin-proteasome-dependent degradation independently of transcriptional alterations. Multi-omics analysis revealed that LSD1 inhibition induced dual reprogramming: transcriptomic activation of the p38MAPK and ubiquitin-proteasome pathways, coupled with metabolomic suppression of the TCA cycle with accumulation of L-proline and other amino acid metabolites. The HDAC inhibitor TSA synergized with methionine restriction to enhance LSD1 acetylation and degradation, whereas K6R/K359R mutations stabilized LSD1, confirming the role of acetylation in proteasomal targeting. Functional validation via colony formation identified LSD1 as a key mediator of methionine restriction; LSD1 knockdown mimicked the growth inhibition of methionine starvation, while its overexpression partially restored proliferation. Collectively, these results establish the methionine-LSD1 axis as a crucial nutrient-sensing mechanism that drives glioma adaptation via epigenetic-metabolic crosstalk. This highlights potential combinatorial therapeutic strategies involving dietary methionine limitation and LSD1 acetylation-targeted therapy to disrupt tumor survival pathways.