Sulfation of chondroitin and bile acids converges to antagonize Wnt/ β-catenin signaling and inhibit APC deficiency-induced gut tumorigenesis

Pengfei Xu; Yue Xi; Jong-Won Kim; Junjie Zhu; Min Zhang; Meishu Xu; Songrong Ren; Da Yang; Xiaochao Ma; Wen Xie

doi:10.1016/j.apsb.2023.12.006

Sulfation of chondroitin and bile acids converges to antagonize Wnt/ β-catenin signaling and inhibit APC deficiency-induced gut tumorigenesis

Acta Pharm Sin B. 2024 Mar;14(3):1241-1256. doi: 10.1016/j.apsb.2023.12.006. Epub 2023 Dec 16.

Authors

Pengfei Xu^{1

2}, Yue Xi¹, Jong-Won Kim¹, Junjie Zhu¹, Min Zhang¹, Meishu Xu¹, Songrong Ren¹, Da Yang¹, Xiaochao Ma¹, Wen Xie^{1

3}

Affiliations

¹ Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
² Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
³ Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Abstract

Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology. 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the primary enzyme to generate the universal sulfonate donor PAPS. The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli (APC) mutation-promoted colonic carcinogenesis has not been reported. Here, we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages, and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer. Gut epithelial-specific heterozygous Apc deficient and Papss2-knockout (Apc^Δgut^-^HetPapss2^Δgut) mice were created, and the phenotypes were compared to the spontaneous intestinal tumorigenesis of Apc^Δgut^-^Het mice. Apc^Δgut^-^HetPapss2^Δgut mice were more sensitive to gut tumorigenesis, which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor (FXR)-transducin-like enhancer of split 3 (TLE3) gene regulatory axis. Chondroitin sulfate supplementation in Apc^Δgut^-^HetPapss2^Δgut mice alleviated intestinal tumorigenesis. In summary, we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin signaling. Chondroitin sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.

Keywords: APC; Bile acids; Chondroitin sulfate; Colon cancer; FXR; PAPSS2; Sulfation; Wnt/β-catenin.