Abstract
Abstract In addition to genetic aberrations, cancer cells harbor global epigenetic abnormalities. Mutant KRAS expression has been shown to induce aberrant DNA methylation and silencing of key tumor suppressors. However, nearly all attempts to directly target oncogenic KRAS have been unsuccessful, yielding an impetus for alternative strategies. Furthermore, in the majority of KRAS-driven tumors, the NF-κB pathway is constitutively active and contributes to cellular transformation. Previously, our lab has shown that knocking out the p65 subunit of NF-κB significantly reduces tumor development in a mouse model of KRAS-induced lung cancer. Here we aim to better understand KRAS-mediated epigenetic reprogramming and uncover novel effects on the NF-κB pathway. Our data suggests that KRAS-mediated epigenetic reprogramming alters the NF-κB pathway to promote transformation. Using the Infinium DNA Methylation Assay, we uncovered genome-wide changes in lung and pancreatic cells expressing KRAS(G12V) compared to wild-type cells. Expression of oncogenic KRAS was accompanied by promoter hypermethylation of tumor suppressors (e.g. FAS, BRCA1, IRAK3) and hypomethylation of oncogenes. Interestingly, we observed hypomethylation at the promoter of the RELB subunit of NF-κB in cells expressing KRAS(G12V). Hypomethylation at the RELB promoter correlated with increased expression of CXCR2, an NF-κB target gene. RNAi against RELB and CXCR2 significantly decreased colony growth in lung and pancreatic cancer cell lines expressing mutant KRAS. Together, these results support a role for KRAS in epigenetic reprogramming and suggest that RELB-dependent CXCR2 expression may be critical in KRAS-driven cancers. RELB and CXCR2 represent potential therapeutic targets that could lead to more effective treatments in the context of KRAS-driven malignancies. Citation Format: Joel Durand, Albert Baldwin. KRAS-mediated epigenetic reprogramming upregulates RELB-dependent CXCR2 expression to promote transformation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1073. doi:10.1158/1538-7445.AM2015-1073
Published Version
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