Inhibition of H3K4 demethylation induces autophagy in cancer cell lines

Epigenetic factors and their associated small molecules have been increasingly recognized as key regulators of the autophagy process. In this study, we demonstrate that 2-PCPA and GSK-LSD1, two inhibitors targeting the histone H3K4 demethylase KDM1A/LSD1, promote autophagy across multiple mammalian cell lines. These compounds induce the accumulation of LC3-II, stimulate the formation of autophagosomes and autolysosomes, and facilitate the degradation of SQSTM1/p62. Notably, 2-PCPA inhibits cell proliferation by inducing cell cycle arrest without triggering cell death. The autophagic effects of 2-PCPA were suppressed by exogenous overexpression of KDM1A/LSD1, suggesting a direct role for this demethylase in regulating autophagy. Moreover, the autophagy induced by 2-PCPA was dependent on LC3-II processing machinery but was not affected by the depletion of BECN1 or ULK1 using siRNA. Transcriptomic analysis revealed that 2-PCPA alters global gene expression, including upregulation of several autophagy-related genes such as SQSTM1/p62. Collectively, our findings suggest that KDM1A/LSD1 inhibitors drive autophagy by modulating autophagy-related gene expression in a BECN1-independent manner.