Stmc-27. novel lysine demethylase kdm1a inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

Glioma Stem Cells (GSCs) play a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we demonstrated that lysine-specific histone demethylase 1A (KDM1A/LSD1) is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and patient-derived GBMs using both in vitro assays and in vivo orthotopic preclinical models. Our results suggested that KDM1A is highly expressed in GSCs and knock down of KDM1A using shRNA reduced GSCs stemness and induced the differentiation. Pharmacological inhibition of KDM1A using NCL-1 and NCD-38 significantly reduced the proliferation, neurosphere formation and induced apoptosis of GSCs with little effect on differentiated cells and KDM1A-knockout cells. In preclinical studies using orthotopic models, NCL-1 and NCD-38 significantly reduced GSC-driven tumor progression and improved mice survival. RNA sequencing analysis showed that KDM1A inhibitors modulate several pathways related to stemness, differentiation and apoptosis. Mechanistic studies showed that KDM1A inhibition induced activation of the unfolded protein response (UPR) pathway. Western blot a...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: STEM CELLS Source Type: research