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PERK/NRF2 and autophagy form a resistance mechanism against G9a inhibition in leukemia stem cells

Ji Eun Jang1, Ju-In Eom2, Hoi-Kyung Jeung2

  • 1Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Journal of Experimental & Clinical Cancer Research : CR
|April 16, 2020
PubMed
Abstract

Insights

Leukemia stem cells (LSCs) resist G9a inhibition via PERK/NRF2 signaling and autophagy. Targeting these pathways could overcome resistance and eliminate LSCs in acute myeloid leukemia (AML) treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • G9a is a potential epigenetic therapy target for acute myeloid leukemia (AML).
  • The impact of G9a inhibition on leukemia stem cells (LSCs), crucial for AML drug resistance and relapse, remains unclear.
  • This study investigates the mechanisms behind LSC resistance to G9a inhibition.

Purpose of the Study:

  • To elucidate the mechanisms of leukemia stem cell (LSC) resistance to G9a inhibition in acute myeloid leukemia (AML).
  • To evaluate the role of the unfolded protein response and autophagy in LSC resistance.
  • To identify potential therapeutic strategies to overcome G9a inhibitor resistance in AML.

Main Methods:

  • Assessed G9a inhibition effects on unfolded protein response and autophagy in AML and LSC-like cell lines, and primary patient samples.
  • Utilized flow cytometry, western blotting, confocal microscopy, and reactive oxygen species (ROS) assays.
  • Investigated the PERK/NRF2 pathway, autophagy flux, and apoptosis induction.

Main Results:

  • G9a inhibition induced apoptosis in AML cell lines but showed limited effect in KG1 LSC-like cells.
  • In KG1 cells, G9a inhibition activated the PERK/NRF2 pathway and HO-1, suppressing ROS and p38 phosphorylation.
  • Inhibition of PERK/NRF2 or autophagy synergistically enhanced G9a inhibitor-induced apoptosis in LSCs, indicating their prosurvival roles.

Conclusions:

  • PERK/NRF2 signaling and autophagy protect LSCs from ROS-induced apoptosis, conferring resistance to G9a inhibitors.
  • Combined inhibition of PERK/NRF2 or autophagy with G9a inhibitors can overcome LSC resistance.
  • These findings suggest potential clinical utility for targeting PERK/NRF2 and autophagy in AML therapy.
Keywords:
AutophagyG9aLeukemia stem cellsPERK/NRF2Resistance

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