Epithelial heme oxygenase-1 enhances colonic tumorigenesis by inhibiting ferroptosis

Abstract

AbstractColorectal cancer has been linked to chronic colitis and red meat consumption, which can increase colonic iron and heme. Heme oxygenase-1 (Hmox1) metabolizes heme and releases ferrous iron, but its role in colonic tumorigenesis is not well-described. Recent studies suggest that ferroptosis, the iron-dependent form of cell death, protects against colonic tumorigenesis. Ferroptosis culminates in excessive lipid peroxidation that is constrained by the antioxidative glutathione pathway. We observed increased mucosal markers of ferroptosis and glutathione metabolism in the setting of murine and human colitis, as well as murine colonic neoplasia. We obtained similar results in murine and human colonic epithelial organoids exposed to heme and the ferroptosis activator erastin, especially induction ofHmox1. RNA sequencing of colonic organoids from mice with deletion of intestinal epithelialHmox1 (Hmox1ΔIEC) revealed increased ferroptosis and activated glutathione metabolism after heme exposure. In a colitis-associated cancer model we observed significantly fewer and smaller tumors inHmox1ΔIECmice compared to littermate controls. Transcriptional profiling ofHmox1ΔIECtumors and tumor organoids revealed increased ferroptosis and oxidative stress markers in tumor epithelial cells. In total, our findings reveal ferroptosis as an important colitis-associated cancer signature pathway, andHmox1as a key regulator in the tumor microenvironment.