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Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

Abstract

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.

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Acknowledgements

This study was supported by the 2014 AACR-AMGEN Inc. fellowship in clinical/translational cancer research (Grant Number: 14-40-11-SARE) and CPRIT training grant (RP140105) awarded to GRS and NCI Grant CA178499 (RKV and AB).

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Correspondence to G R Sareddy or R K Vadlamudi.

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Sareddy, G., Viswanadhapalli, S., Surapaneni, P. et al. Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway. Oncogene 36, 2423–2434 (2017). https://doi.org/10.1038/onc.2016.395

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