Histone lysine demethylase 1A inhibitors, seclidemstat and tranylcypromine, induce astrocytogenesis in rat neural stem cells

Identifying the molecules that control neural stem cell (NSC) fate would revolutionize treatment strategies for neurodegenerative diseases. Histone lysine demethylase 1A (KDM1A) demethylates the mono- and di-methyl groups of histone 3 lysine 4 (H3K4) and H3K9 and plays an essential role in NSC proliferation. In this study, we investigated the effects of Seclidemstat (SP-2577), a reversible KDM1A inhibitor, and tranylcypromine (TCP), a monoamine oxidase inhibitor and recently known as an irreversible histone lysine demethylase 1A inhibitor, on NSCs. SP-2577 and TCP increased glial fibrillary acidic protein expression (GFAP), decreased βIII-tubulin (TUBB3) expression, and phosphorylated signal transducer and activator of transcription 3 (STAT3) in rat NSCs. SP-2577 and TCP enhanced the transcription of Gfap and reduced Tubb3 transcription. Furthermore, SP-2577 increased the transcription levels of interleukin-6 and leukemia inhibitory factor, while TCP induced the transcription level of fibroblast growth factor 2. Therefore, we show that the KDM1A inhibitors, SP-2577 and TCP, induce astrocytogenesis in rat NSCs. These findings suggest that KDM1A is a target for regulating NSCs fate and provide insights into the molecular mechanisms underlying neurodevelopmental processes and epigenetics.