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 &amp
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  -