TY - JOUR AU - Sareddy, G.R. AU - Viswanadhapalli, S. AU - Surapaneni, P. AU - Suzuki, T. AU - Brenner, A. AU - Vadlamudi, R.K. PY - 2017// TI - Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway T2 - Oncogene JO - Oncogene SP - 2423 EP - 2434 VL - 36 IS - 17 KW - Animals KW - Apoptosis/*drug effects KW - Cell Differentiation/*drug effects KW - Cell Line KW - Tumor KW - Cell Survival/drug effects KW - Cell Transformation KW - Neoplastic KW - Disease Progression KW - Enzyme Inhibitors/*pharmacology KW - Gene Expression Regulation KW - Neoplastic/drug effects KW - Glioma/*pathology KW - Histone Demethylases/*antagonists & KW - inhibitors KW - Mice KW - Neoplastic Stem Cells/*drug effects/metabolism/pathology KW - Signal Transduction/drug effects KW - Survival Analysis KW - Transcription KW - Genetic/drug effects KW - Unfolded Protein Response/*drug effects AB - Glioma stem cells (GSCs) have 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 showed that lysine demethylase KDM1A 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 knockdown of KDM1A using shRNA-reduced GSCs stemness and induced the differentiation. Pharmacological inhibition of KDM1A using NCL-1 and NCD-38 significantly reduced the cell viability, neurosphere formation and induced apoptosis of GSCs with little effect on differentiated cells. In preclinical studies using orthotopic models, NCL-1 and NCD-38 significantly reduced GSCs-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 inhibitors induce activation of the unfolded protein response (UPR) pathway. These results strongly suggest that selective targeting of KDM1A using NCL-1 and NCD-38 is a promising therapeutic strategy for elimination of GSCs. SN - 0950-9232 UR - http://www.ncbi.nlm.nih.gov/pubmed/27893719 UR - PM:27893719 N1 - PMID:27893719 ID - Sareddy_etal2017 ER -