Lipidomic profiling reveals lipid regulation by a novel LSD1 inhibitor treatment

Abstract

Lipid metabolic alterations are associated with cancer progression. Lysine-specific demethylase 1 (LSD1) plays a crucial role in cancer and has become a promising target for cancer therapy. However, the effect of LSD1 on lipid metabolism remains unclear. In the present study, we used a LC-MS/MS-based lipidomics approach to investigate the impact of LSD1 on cancer cell lipid metabolism using ZY0511, a specific LSD1 inhibitor developed by our group as a specific probe. ZY0511 profoundly modified the human colorectal and cervical cancer cell lipid metabolism. A total of 256 differential metabolites were identified in HeLa cells, and 218 differential metabolites were identified in HCT116 cells, respectively. Among these lipid metabolites, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and sphingomyelin (SM) were downregulated by ZY0511. In contrast, ceramide (Cer) and a small portion of glycerophospholipids such as phosphatidylinositol and phosphatidylethanolamine were upregulated by ZY0511. These results revealed a disturbance in sphingolipids (SPs) and glycerophospholipids, which may be correlated with the progression of cancer. Furthermore, a marked increase in Cer and prominent decrease in SM were consistent with the upregulated expression of key enzymes in the Cer synthesis process including de novo synthesis, hydrolysis of SM and the salvage pathway after ZY0511 exposure. In conclusion, our research reveals a link between LSD1 and lipid metabolism in cancer cells, offering more comprehensive evidence for the application of LSD1 inhibitors for cancer therapy. The underlying mechanisms of how the LSD1 inhibitor regulates lipid metabolism warrant further investigation.