GSE135605
Remodelling of H3K4me3 in response to long term drug treatment or oncogenic stress
Accumulating evidence indicates adaptive cellular reprogramming is a major contributor to disease recurrence and acquired drug resistance in cancer. Here we show that chronic drug exposure results in a multi-state metabolic and epigenetic adaption that allows cancer cells to regain proliferative capacity and eventually develop permanent drug resistance. Specifically, the escape from the previously described slow cycling induced drug tolerant cell state is driven by transiently increased expression of O-GlcNAc transferase (OGT) linking metabolic to epigenetic changes by facilitating global H3K4me3 remodeling. This adaptive process can be blocked by genetic or pharmacological inhibition of OGT or concurrent activation of AMPK to prevent metabolic adaption, subsequent epigenetic remodeling and permanent acquired drug resistance. This novel metabolic and epigenetic remodeling process is also observed following oncogene induced stress and the OGT dependence of this adaptive process uncovered promising targets for combination therapy with current standard of care drugs that could significantly increase response duration and patient outcomes. Overall design: Experiments compare the H3K4me3 profiles of the BRAF mutant melanoma cell line WM164 without treatment or under long term exposure to sub lethal doses of the BRAF inhibitor dabrafenib. Additionally, H3K4me3 profiles of the BRAF mutant melanoma cell line WM164 overexpressing either GFP or NRAS Q61K are compared. All samples were prepared in duplicates.