Extracellular matrix detached cancer cells resist oxidative stress by increasing histone demethylase KDM6 activity

Epithelial cancer cells rely on the extracellular matrix (ECM) attachment in order to spread to other organs. Detachment from the ECM is necessary for these cells to seed in other locations. When the attachment to the ECM is lost, cellular metabolism undergoes a significant shift from oxidative metabolism to glycolysis. Additionally, the cancer cells become more dependent on glutaminolysis to avoid a specific type of cell death known as anoikis, which is associated with ECM detachment. In our recent study, we observed increased expression of H3K27me3 demethylases, specifically KDM6A/B, in cancer cells that were resistant to anoikis. Since KDM6A/B is known to regulate cellular metabolism, we investigated the effects of suppressing KDM6A/B with GSK-J4 on the metabolic processes in these anoikis-resistant cancer cells. Our results from untargeted metabolomics revealed a profound impact of KDM6A/B inhibition on various metabolic pathways, including glycolysis, methyl histidine, spermine, and glutamate metabolism. Inhibition of KDM6A/B led to elevated reactive oxygen species (ROS) levels and depolarization of mitochondria, while reducing the levels of glutathione, an important antioxidant, by diminishing the intermediates of the glutamate pathway. Glutamate is crucial for maintaining a pool of reduced glutathione. Furthermore, we discovered that KDM6A/B regulates the key glycolytic genes expression like hexokinase, lactate dehydrogenase, and GLUT-1, which are essential for sustaining glycolysis in anoikis-resistant cancer cells. Overall, our findings demonstrated the critical role of KDM6A/B in maintaining glycolysis, glutamate metabolism, and glutathione levels. Inhibition of KDM6A/B disrupts these metabolic processes, leading to increased ROS levels and triggering cell death in anoikis-resistant cancer cells.