4SC-202 induces apoptosis in myelodysplastic syndromes and the underlying mechanism
Epigenetic modifications play crucial roles in controlling the self-renewal and differentiation of hematopoiesis. 4SC-202, a singular inhibitor of histone lysine-specific demethylase 1 (LSD1) and sophistication I histone deacetylases (HDACs), is really a potential therapeutic agent to deal with myelodysplastic syndrome (MDS). However, it remains unclarified from the mechanism of 4SC-202. Within the study, we discovered that 4SC-202 treatment could hinder cell viability, induce apoptosis and cause G2/M cell cycle arrest in MDS cell line SKM-1. Heme oxygenase-1 (HO-1) was correlated with disease progression and chemotherapy resistance. Here, we reported that 4SC-202 could lower-regulate the expression of HO-1, or more-regulating HO-1 could considerably attenuate the 4SC-202-caused apoptosis in SKM-1 cells. Additionally, the activation of NF-?B path was covered up by 4SC-202, while up-regulating HO-1 considerably weakened the 4SC-202-caused suppression from the NF-?B path, therefore attenuating the effectiveness of 4SC-202. However, lower-regulating HO-1 enhanced the sensitivity of 4SC-202 against SKM-1 cells. Furthermore, SKM-1 cells were transfected with HO-1 overexpression lentivirus, subsequently injected in to the tail vein of NOD/SCID rodents, adopted by administration of 4SC-202 in rodents. Consequently, up-regulation HO-1 could partly attenuate 4SC-202-covered up MDS cells development in NOD/SCID rodents. To conclude, 4SC-202 could induce apoptosis through the NF-?B path, and our present finding may give a novel therapeutic technique for MDS.