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Abstract
Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 differentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in differentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream effector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer.
Highlights
Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer
Given the essential role of oncogenic KRAS in the great majority of pancreatic cancer[15,29], we investigated whether the presence of an activating KRAS mutation correlates with specific patterns of global DNA methylation
As the pancreatic cancer cell lines were transduced with non-silencing (NS) shRNA, which could potentially affect the methylome of the transduced cells, we performed the same analysis while excluding these cells (Supplementary Fig. S2)
Summary
Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 differentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS-mediated DNA methylation are stochastic and independent of canonical downstream effector signaling These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. We have previously shown that mutant KRAS drives distinct molecular changes in pancreatic[29] and lung[30] cancer cells It remains unclear whether these molecular changes are associated with epigenetic changes. We perform a genome-scale analysis using KRAS-mutant human pancreatic and lung cancer cell lines to investigate whether knock-down or overexpression of mutant KRAS as well as pharmacological inhibtion of ERK correlates with differential DNA methylation. We found that ERK inhibition did not reverse the great majority of KRAS-mediated methylation changes, suggesting that ERK is not a main driver for KRAS-mediated DNA methylation changes
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