Intestinal Sulfation is Essential to Protect Against Colitis‐Associated Colonic Carcinogenesis

Abstract

Sulfation is a conjugation reaction essential for numerous biochemical and cellular functions in mammals. The 3′-phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the key enzyme to generate PAPS, which is the universal sulfonate donor for all sulfation reactions. The goal of this study is to determine whether and how PAPSS2 plays a role in colitis and colitis-associated colonic carcinogenesis. The expression of PAPSS2 is decreased in the colon cancers of mice and humans. The lower expression of PAPSS2 in colon cancer patients is correlated with worse survival. In mice, intestinal ablation of the Papss2 gene (Papss2ΔIE) promoted colitis and associated colon cancer by damaging the intestinal mucosal barrier, increasing intestinal permeability and bacteria infiltration, and worsening the intestinal tumor microenvironment. Mechanistically, the Papss2ΔIE mice exhibited reduced intestinal sulfomucin content. Metabolomic analyses revealed the accumulation of bile acids including farnesoid X receptor (FXR) antagonist bile acid tauro-β-muricholic acid (T-β-MCA), as well as deficiency in the formation of bile acid-sulfates in the colon of Papss2ΔIE mice. In summary, we have uncovered the role of PAPSS2-mediated sulfation in colitis and associated colonic carcinogenesis. Intestinal sulfation may represent a potential diagnostic marker, and PAPSS2 may serve as a potential therapeutic target for inflammatory bowel disease and colon cancer.