Inhibition of H3K4 demethylation induces autophagy in cancer cell lines

Epigenetic factors and related small molecules have emerged to be strongly involved in autophagy process. Here we report that two inhibitors of histone H3K4 demethylase KDM1A/LSD1, 2-PCPA and GSK-LSD1, are able to induce autophagy in multiple cell lines. The two small molecules induced accumulation of LC3II, formation of autophagosome, fusion of autophagosome with lysosome and SQSTM1/p62 degradation. 2-PCPA treatment inhibits cell proliferation through cell cycle arrest but not inducing cell death. Exogenous expression of KDM1A/LSD1 impaired the autophagic phenotypes triggered by 2-PCPA. The autophagy induced by 2-PCPA requires LC3-II processing machinery. But depletion of BECN1 and ULK1 with siRNA did not affect the LC3-II accumulation triggered by 2-PCPA. 2-PCPA treatment induces the change of global gene expression program, including a series of autophagy-related genes, such as SQSTM1/p62. Taken together, our data indicate that KDM1A/LSD1 inhibitors induce autophagy through affecting the expression of autophagy-related genes and in a BECN1-independent manner. Overall design: Examination of RNA from U2OS cell with 10 kinds of small molecules treatment