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Intestinal Sulfation is Essential to Protect Against Colitis‐Associated Colonic Carcinogenesis
Author(s) -
Xu Pengfei,
Xi Yue,
Zhu Junjie,
Zhang Min,
Luka Zigmund,
Stolz Donna,
Cai Xinran,
Xie Yang,
Xu Meishu,
Ren Songrong,
Huang Zhiying,
Yang Da,
York John,
Ma Xiaochao,
Xie Wen
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04001
Subject(s) - colitis , sulfation , colorectal cancer , farnesoid x receptor , bile acid , azoxymethane , carcinogenesis , inflammatory bowel disease , cancer research , chemistry , medicine , gastroenterology , cancer , biochemistry , disease , nuclear receptor , transcription factor , gene
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 ( Papss2 ΔIE ) 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 Papss2 ΔIE 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 Papss2 ΔIE 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.