RNA sequencing of colorectal adenocarcinoma DLD1 cell lines treated with siPKN2.
Inflammation is a major driver of tumorigenesis and chronic colitis is a significant risk factor for developing colorectal cancer (CRC). Here, we identify the Rho regulated kinase PKN2 as a new tumour suppressor in colitis-associated CRC. Using conditional global and epithelial-specific knockout mice, we show that loss of PKN2 sensitises mice to inflammatory bowel injury and results in increased colorectal adenoma formation in a colitis-associated CRC model. Tumour burden tightly correlates with colitis disease severity suggesting elevated inflammatory tissue injury underlies tumour promotion in PKN2-targeted mice. Mechanistically, PKN2 localises to epithelial tight junctions and is required for maintaining effective barrier integrity in vivo, in intestinal organoids and in CRC cell models. We identify several candidate junctional substrates of PKN2 including S737 of the PP1 regulator ASPP2. These findings establish PKN2 as a functional regulator of gut barrier integrity encoded at genomic loci previously associated with bowel inflammation and tumour suppression in both humans and mice.