oicr-9429 has been researched along with Neoplasms* in 1 studies
1 other study(ies) available for oicr-9429 and Neoplasms
Article | Year |
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Genotoxic stress-triggered β-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasis.
The mechanisms underlying how cells subjected to genotoxic stress reestablish reduction-oxidation (redox) homeostasis to scavenge genotoxic stress-induced reactive oxygen species (ROS), which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we report that, via a TCF-independent mechanism, genotoxic stress induces the enrichment of β-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2me1/H3R2me2s-induced transcriptional activation by the recruitment of the WDR5/MLL methyltransferase complexes and concomitant H3K4 methylation at the promoters of multiple genes in GSH-metabolic cascade. Treatment with OICR-9429, a small-molecule antagonist of the WDR5-MLL interaction, inhibits the β-catenin/JDP2/PRMT5 complex-reestablished GSH metabolism, leading to a lethal increase in the already-elevated levels of ROS in the genotoxic-agent treated cancer cells. Therefore, our results unveil a plausible role for β-catenin in reestablishing redox homeostasis upon genotoxic stress and shed light on the mechanisms of inducible chemotherapy resistance in cancer. Topics: A549 Cells; Animals; beta Catenin; Biphenyl Compounds; Cell Line, Tumor; Chromatin; Dihydropyridines; DNA Damage; Female; Glutathione; Histone-Lysine N-Methyltransferase; Histones; Homeostasis; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Myeloid-Lymphoid Leukemia Protein; Neoplasms; Promoter Regions, Genetic; Protein Interaction Domains and Motifs; Protein-Arginine N-Methyltransferases; Reactive Oxygen Species; Repressor Proteins; Transcriptional Activation | 2019 |