Comprehensive bioinformatic analyses of KRAS mutations and deciphering chromatin modification landscape of Caveolin-1 gene by lipid raft destabilization induced modulation of RAS-MAPK axis in colon cancer

Abstract

Ras signaling contributes to multiple components of cellular functions. To gain insight into the role of KRAS mutant isoforms, we bioinformatically analyzed and noticed that KRAS mutations at G12V, G12D, and G13D positions are prominent in colorectal adenoma and carcinoma. The bioinformatic analysis indicates that KRAS mutations affect MAPK signaling cascades despite other signaling pathways. Lipid rafts orchestrate many signaling pathways on the plasma membrane and one of those works via the RAS/ERK axis to activate gene expression. Herein, we show that lipid raft-RAS/ERK modulates gene expression by differentially altering active H3K4me3 and H3K9acS10P, and repressive H3K9me3 and H3K27me3 marks, and further, we have deciphered distinct expression pattern of Caveolin-1 (CAV1) in constitutive KRAS versus lipid raft disruption induced KRAS signaling in colon cancer cells, HCT-15. CAV1 gene expression is upregulated by differential enrichment of H3K4me2, H3K4me3, and H3K9acS10p, depending on which component of the lipid raft/RAS/ERK axis is blocked. The enhancement of transcription of the CAV1 gene is associated with very high occupancy of H3K4me3 and H3K9acS10p and very low H3K9me3 marks in its promoter region. Thus we conclude that genetic mutation in KRAS and distinct association of lipid raft with KRAS contributes to colon cancer progression; however, lipid raft association/dissociation regulates the paradoxical function of genes, for example, CAV1, by epigenetic modulations.