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PERK/NRF2 and Autophagy Form a Resistance Mechanism Against G9a Inhibition in Leukemia Stem Cells

Authors
 Ji Eun Jang  ;  Ju-In Eom  ;  Hoi-Kyung Jeung  ;  Haerim Chung  ;  Yu Ri Kim  ;  Jin Seok Kim  ;  June-Won Cheong  ;  Yoo Hong Min 
Citation
 JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, Vol.39(1) : 66, 2020-04 
Journal Title
 JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 
ISSN
 0392-9078 
Issue Date
2020-04
Keywords
Autophagy ; G9a ; Leukemia stem cells ; PERK/NRF2 ; Resistance
Abstract
Background: The histone methyltransferase G9a has recently been identified as a potential target for epigenetic therapy of acute myeloid leukemia (AML). However, the effect of G9a inhibition on leukemia stem cells (LSCs), which are responsible for AML drug resistance and recurrence, is unclear. In this study, we investigated the underlying mechanisms of the LSC resistance to G9a inhibition. Methods: We evaluated the effects of G9a inhibition on the unfolded protein response and autophagy in AML and LSC-like cell lines and in primary CD34+CD38- leukemic blasts from patients with AML and investigated the underlying mechanisms. The effects of treatment on cells were evaluated by flow cytometry, western blotting, confocal microscopy, reactive oxygen species (ROS) production assay. Results: The G9a inhibitor BIX-01294 effectively induced apoptosis in AML cell lines; however, the effect was limited in KG1 LSC-like cells. BIX-01294 treatment or siRNA-mediated G9a knockdown led to the activation of the PERK/NRF2 pathway and HO-1 upregulation in KG1 cells. Phosphorylation of p38 and intracellular generation of reactive oxygen species (ROS) were suppressed. Pharmacological or siRNA-mediated inhibition of the PERK/NRF2 pathway synergistically enhanced BIX-01294-induced apoptosis, with suppressed HO-1 expression, increased p38 phosphorylation, and elevated ROS generation, indicating that activated PERK/NRF2 signaling suppressed ROS-induced apoptosis in KG1 cells. By contrast, cotreatment of normal hematopoietic stem cells with BIX-01294 and a PERK inhibitor had no significant proapoptotic effect. Additionally, G9a inhibition induced autophagy flux in KG1 cells, while autophagy inhibitors significantly increased the BIX-01294-induced apoptosis. This prosurvival autophagy was not abrogated by PERK/NRF2 inhibition. Conclusions: PERK/NRF2 signaling plays a key role in protecting LSCs against ROS-induced apoptosis, thus conferring resistance to G9a inhibitors. Treatment with PERK/NRF2 or autophagy inhibitors could overcome resistance to G9a inhibition and eliminate LSCs, suggesting the potential clinical utility of these unique targeted therapies against AML.
Files in This Item:
T202001553.pdf Download
DOI
10.1186/s13046-020-01565-3
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Yu Ri(김유리) ORCID logo https://orcid.org/0000-0001-5505-0142
Kim, Jin Seok(김진석) ORCID logo https://orcid.org/0000-0001-8986-8436
Min, Yoo Hong(민유홍) ORCID logo https://orcid.org/0000-0001-8542-9583
Jang, Ji Eun(장지은) ORCID logo https://orcid.org/0000-0001-8832-1412
Cheong, June-Won(정준원) ORCID logo https://orcid.org/0000-0002-1744-0921
Chung, Hae Rim(정해림) ORCID logo https://orcid.org/0000-0002-7926-9285
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/176174
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