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 un...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-Het)Papss2^(Δgut))mice were created,and the phenotypes were compared to the spontaneous intestinal tumorigenesis of Apc^(Δgut-Het)mice.Apc^(Δgut-Het)Papss2^(Δgutmice) 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-Het)Papss2^(Δgutmice) 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.展开更多
Background and Aim:Sulfotransferase(SULT)-mediated sulfation and steroid sulfatase(STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and ex...Background and Aim:Sulfotransferase(SULT)-mediated sulfation and steroid sulfatase(STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and exogenous molecules.STS catalyzes the hydrolysis of steroid sulfates to form hydroxysteroids.Oxygenated cholesterol derivative oxysterols are known to be endogenous ligands of the liver X receptor(LXR),a nuclear receptor with anti-cholestasis activity,whereas the sulfated oxysterols antagonize LXR signaling.The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS.The aim of this study is to determine whether STS can alleviate cholestasis by increasing the activity of LXR.Methods:Liver-specific STS transgenic mice were created and subject to the lithocholic acid(LCA)-induced model of cholestasis.Results:Transgenic overexpression of STS in the liver promoted bile acid elimination and alleviated LCAinduced cholestasis.The protective effect of the STS transgene was associated with the activation of LXR and induction of LXR target genes,likely because of the increased conversion of the antagonistic oxysterol sulfates to the agonistic oxysterols.Conclusions:STS has a novel function in controlling the homeostasis of bile acids by regulating endogenous LXR ligands.展开更多
基金supported by NIH grants DK117370,DK135538,and ES030429(to Wen Xie,US)a Pilot&Feasibility grant(to Pengfei Xu,US)from the Pittsburgh Liver Research Center funded by NIH grant P30DK120531NIH shared instrumentation grant:Olympus FV3000 Confocal Microscope SIG:NIH S10OD030254-01A1。
文摘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-Het)Papss2^(Δgut))mice were created,and the phenotypes were compared to the spontaneous intestinal tumorigenesis of Apc^(Δgut-Het)mice.Apc^(Δgut-Het)Papss2^(Δgutmice) 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-Het)Papss2^(Δgutmice) 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.
基金This work was supported in part by the National Institutes of Health grants DK083952 and HD073070(to W.X.).
文摘Background and Aim:Sulfotransferase(SULT)-mediated sulfation and steroid sulfatase(STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and exogenous molecules.STS catalyzes the hydrolysis of steroid sulfates to form hydroxysteroids.Oxygenated cholesterol derivative oxysterols are known to be endogenous ligands of the liver X receptor(LXR),a nuclear receptor with anti-cholestasis activity,whereas the sulfated oxysterols antagonize LXR signaling.The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS.The aim of this study is to determine whether STS can alleviate cholestasis by increasing the activity of LXR.Methods:Liver-specific STS transgenic mice were created and subject to the lithocholic acid(LCA)-induced model of cholestasis.Results:Transgenic overexpression of STS in the liver promoted bile acid elimination and alleviated LCAinduced cholestasis.The protective effect of the STS transgene was associated with the activation of LXR and induction of LXR target genes,likely because of the increased conversion of the antagonistic oxysterol sulfates to the agonistic oxysterols.Conclusions:STS has a novel function in controlling the homeostasis of bile acids by regulating endogenous LXR ligands.