首页|Sulfation of chondroitin and bile acids converges to antagonize Wnt/β-catenin signaling and inhibit APC deficiency-induced gut tumorigenesis
Sulfation of chondroitin and bile acids converges to antagonize Wnt/β-catenin signaling and inhibit APC deficiency-induced gut tumorigenesis
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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△gut-Het Papss2△gut)mice were created,and the phenotypes were compared to the spontaneous intestinal tumorigenesis of Apc△gut-Het mice.Apc△gut-Het Papss2△gut 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 supplemen-tation in Apc△gut-HetPapss2△gut 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 sul-fate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.
Center for Pharmacogenetics and Department of Pharmaceutical Sciences,University of Pittsburgh,Pittsburgh,PA 15261,USA
Department of Hepatobiliary and Pancreatic Surgery,Zhongnan Hospital of Wuhan University,School of Pharmaceutical Sciences,Wuhan University,Wuhan 430071,China
Department of Pharmacology & Chemical Biology,University of Pittsburgh,Pittsburgh,PA 15261,USA
美国国立卫生研究院项目美国国立卫生研究院项目美国国立卫生研究院项目Pilot & Feasibility grant(to Pengfei Xu,US)from the Pittsburgh Liver Research Center funded by NIH grantNIH shared instrumentation grant:Olympus FV3000 Confocal Microscope SIG
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