LSD1 Inhibitor 4SC-202 Inducing Apoptosis in Myelodysplastic Syndrome Cells Via NF-κb-HO-1 Pathway

Aims: Human histone lysine-specific demethylase 1(LSD1) inhibit gene transcription and thereby block myeloid differentiation, apoptosis and cell cycle in AML. 4SC-202, a novel inhibitor of LSD1, is potential therapeutic agent for treating Myelodysplastic syndrome, while its mechanism of action remains unclear.

Mainlymethod: In the study, LSD1 and HO-1 gene expression were detected in MDS/AML patients. After MDS cell line SKM-1 was treated with 4SC-202, cell viability, apoptosis and cell cycle were detected by CCK-8 or FACS. Lastly, western blotting analyzed that the agent caused the change of the related cellular function protein in SKM-1 cells.

Key findings: We found that LSD1 and HO-1 were overexpression in MDS/AML patients. LSD1 inhibitor 4SC-202 inhibited cell viability. The agent induced apoptosis by up-regulated BAX and cleaved caspase3/9 as well as down-regulated BCL-2, arrested cell cycle in the G2/M phase by down-regulated CDK1 and up-regulated p21, as well as inhibited activation of the NF-κB pathway and decreased HO-1. LSD1 and HO-1 expression were decreased after exposure with the NF-κB inhibitor OBY11-7082. Silencing LSD1 by LSD1 siRNA hardly caused apoptosis in SKM-1 cells, while the combination of Bay11-7082 and silencing LSD1 significantly decreased LSD1 and HO-1 expression and further increased apoptosis. While up-regulated HO-1 significantly limited the 4SC-202-induced down-regulation of BCL-2, up-regulation of cleaved caspase 3/9 and suppressed activation of NF-κB pathway as well as thereby attenuated the agent efficacy.

Significant: In conclusion, LSD1 inhibitor 4SC-202 induced apoptosis through the NF-κB-mediated HO-1 pathway. LSD1 might be a potential target for the treatment of MDS.