Hepatocellular carcinoma(HCC)is one of the common most malignant tumors.This study aimed to determine the in vitro and in vivo anticancer activity of cordycepin and elucidate its mechanism of action.The results of in ...Hepatocellular carcinoma(HCC)is one of the common most malignant tumors.This study aimed to determine the in vitro and in vivo anticancer activity of cordycepin and elucidate its mechanism of action.The results of in vitro and in vivo studies revealed that cordycepin inhibited proliferation and migration in HepG-2 cells and inhibited the growth of HepG-2 xenograft-bearing nude mice by inducing apoptosis.Transcriptome sequencing analysis revealed a total of 403 differential genes,which revealed that cordycepin may play an anti-HCC role by regulating Hippo signaling pathway.The regulatory effects of cordycepin on the Hippo signaling pathway was further investigated using a YAP1 inhibitor.The results demonstrated that cordycepin upregulated the expression of MST1 and LAST1,and subsequently inhibited YAP1,which activated the Hippo signaling pathway.This in turn downregulated the expression of GBP3 and ETV5,and subsequently inhibited cell proliferation and migration.Additionally,YAP1 regulated the expression of Bax and Bcl-2,regulated the mitochondrial apoptotic pathway,and induced apoptosis by upregulating the expression of the caspase-3 protein.In summary,this study reveals that cordycepin exerts its anti-hepatocarcinoma effect through regulating Hippo signaling pathway,and GBP3 and ETV5 may be potential therapeutic targets for hepatocarcinoma.展开更多
Objective:To explore the mechanism of Huatan Sanjie Fang(HTSJ)in regulating goiter in Graves'disease(GD)mice by detecting key factors of the Hippo signaling pathway.Methods:A mouse model of GD was established by i...Objective:To explore the mechanism of Huatan Sanjie Fang(HTSJ)in regulating goiter in Graves'disease(GD)mice by detecting key factors of the Hippo signaling pathway.Methods:A mouse model of GD was established by injecting Ad-TSHR289 adenovirus into the bilateral quadriceps femoris of female mice.Successful mouse models were then randomly divided into a model group,methimazole(MMI)group,and HTSJ group,and fed with deionized water,MMI(4.5 mg/kg per day),and HTSJ(35.10 g/kg per day),respectively,for 10 weeks.Histopathological changes of the thyroid gland were subsequently observed by hematoxylin-eosin staining.Radioimmunoassay was used to detect serum total thyroxine(T4)and thyrotrophin-receptor antibody(TRAb)levels.The relative expression of mRNA of Mst1,YAP,and TAZ were detected by quantitative real-time polymerase chain reaction,while the protein expression of Mst1,YAP,TAZ,pMst1,and pYAP were detected by western blot.Results:After 10 weeks of drug intervention,goiter and other pathological changes in the HTSJ group significantly improved compared with the model group,and the levels of serum T4 and TRAb significantly decreased(P=.002,P<.001,respectively).Decreased mRNA expression of Mst1,YAP,and TAZ,the key factors of the Hippo signaling transduction pathway,was also observed(P=.002,P=.022,P<.001,respectively).In contrast,protein expression of Mst1(P=.046),pMst1(P=.026),and p YAP(P=.004)increased,while protein expression of YAP and TAZ decreased(P=.041,P<.001,respectively).Conclusion:HTSJ can effectively improve goiter in GD mice through the Hippo signaling pathway.展开更多
OBJECTIVE To investigate the effect of scutellarin on the apoptosis of human colorectal cancer cells via the Hippo signaling pathway in vitro.METHODS MTT colorimetric method was used to detect the influence of scutell...OBJECTIVE To investigate the effect of scutellarin on the apoptosis of human colorectal cancer cells via the Hippo signaling pathway in vitro.METHODS MTT colorimetric method was used to detect the influence of scutellarin on the survival rate of HCT116 cells.And the effect of scutellarin at various concentrations on cell morphology was observed by microscopy.Cell scratch experiment was used to detect the influence of scutellarin on the migration of HCT116 cells.Hoechst33342/PI double staining method was used to detect the effect of scutellarin on the apoptosis of HCT116 cells.Western blotting method was used to assess the action of scutellarin on the expressions of Hippo signaling pathway-related proteins Mst1,Lats1,YAP1,p-YAP(Ser127),TAZ,and its downstream effector proteins c-Myc and cyclin D1,as well as apoptosis-related proteins Bcl-2 and Bax in HCT116 cells.RESULTS Scutellarin significantly affected the morphology of HCT116 cells and reduced the survival rate of HCT116 cells.Hoechst33342/PI double staining showed that scutellarin effectively induced the apoptosis of HCT116 cells.Western blotting analysis showed that the expression levels of Hippo signaling pathway-related proteins Mst1,Lats1,YAP1,TAZ and its downstream effector proteins c-Myc,cyclin D1 were down-regulated in a concentration-dependent manner by scutellarin,and the expression of p-YAP(ser127)was up-regulated.Moreover,scutellarin substantially lessened the expression level of apoptosis-related protein Bcl-2,and promoted the protein level of Bax.CONCLUSION Scutellarin may inhibit the proliferation and migration of HCT116 cells,while induce its apoptosis,potentially by activation of Hippo signaling pathway.展开更多
Regulation of the Hippo signaling pathway is essential for normal organ growth and tissue homeostasis.The proteins that act to regulate this pathway are important for ensuring proper function and cellular location.Deu...Regulation of the Hippo signaling pathway is essential for normal organ growth and tissue homeostasis.The proteins that act to regulate this pathway are important for ensuring proper function and cellular location.Deubiquitinases(DUBs)are a family of proteases that act upon many proteins.While ubiquitinases add ubiquitin and target proteins for degradation,DUBs act by removing ubiquitin(Ub)moieties.Changes in ubiquitin chain topology results in the stabilization of proteins,membrane trafficking,and the alteration of cellular localization.While the roles of these proteins have been well established in a cancer setting,their convergence in cancer is still under investigation.In this review,we discuss the roles that DUBs play in the regulation of the Hippo signaling pathway for homeostasis and disease.展开更多
Yes-associated protein 1(YAP1)is a downstream effector of the Hippo signaling pathway,and it is involved in tumorigenesis,tissue repair,growth,and development.In this review,the biological roles and the mechanisms of ...Yes-associated protein 1(YAP1)is a downstream effector of the Hippo signaling pathway,and it is involved in tumorigenesis,tissue repair,growth,and development.In this review,the biological roles and the mechanisms of YAP1 in mediating stem cell fate decisions are discussed,including cell proliferation,differentiation,and apoptosis.In general,YAP1 promotes the proliferation and differentiation of stem cells,including embryonic stem cells and adult stem cells.It inhibits apoptosis by binding to the transcription factors,e.g.,transcriptional enhanced associate domain(TEAD),Smad,runt-related transcription factor 1/2,p73,p63,and Erb84,to maintain tissue homeostasis.The translocalization of YAP1 in cellular nuclei and the phosphorylation in the cytoplasm work as important and unusual events for the activation of YAP1.Moreover,YAP1 serves as the crosstalk for the Hippo pathway and other signaling pathways,including the Wnt and Notch pathways.It is highlighted in this review that YAP1 is an essential regulator for stem cells that have significant applications in regenerative medicine and reproductive medicine.展开更多
Polycystic ovary syndrome (PCOS) is a heterogeneous reproductive disease that can cause infertility. The Hippo signaling pathway, a network highly conserved throughout evolution, maintains the balance between follicle...Polycystic ovary syndrome (PCOS) is a heterogeneous reproductive disease that can cause infertility. The Hippo signaling pathway, a network highly conserved throughout evolution, maintains the balance between follicle proliferation and dormancy. Dynamic changes in primordial follicles cannot occur without the participation of biological signals and mechanical force;however, little is known about the mechanism by which biomechanical signaling triggers PCOS, especially in the context of primordial follicle development. To investigate the contribution of mechanical stress and the Hippo signaling pathway to the onset of PCOS, we searched the literature via the PubMed database, and inclusion and exclusion criteria were established to ensure the rigor of this research. We eventually included 54 publications in which Hippo signaling and mechanical force were suggested to play a vital role in the development of primordial follicles as well as elucidate the pathogenesis of PCOS. The Hippo pathway modulating follicle growth can be perturbed via extracellular mechanical stress caused by the stiff ovarian cortical environment in PCOS. Clinical intervention targeting the Hippo pathway can alter the activity of core Hippo members, such as the Yes-associated protein/transcriptional co-activator PDZ-binding motif complex. In some patients with PCOS, follicle overactivation can be attributed to the dysfunction of Hippo signal transduction. PCOS, a condition with various patterns, cannot be accurately explained by a single, specific mechanism. The present review identifies potential targets and therapeutic strategies for PCOS.展开更多
Large tumor suppressor 1(LATS1)is the key kinase controlling activation of Hippo signalling pathway.Post-translational modifications of LATS1 modulate its kinase activity.However,detailed mechanism underlying LATS1 st...Large tumor suppressor 1(LATS1)is the key kinase controlling activation of Hippo signalling pathway.Post-translational modifications of LATS1 modulate its kinase activity.However,detailed mechanism underlying LATS1 stability and activation remains elusive.Here we report that LATS1 is acetylated by acetyltransferase CBP at K751 and is deacetylated by deacetylases SIRT3 and SIRT4.Acetylation at K751 stabilized LATS1 by decreasing LATS1 ubiquitination and inhibited LATS1 activation by reducing its phosphorylation.Mechanistically,LATS1 acetylation resulted in inhibition of YAP phosphorylation and degradation,leading to increased YAP nucleus translocation and promoted target gene expression.Functionally,LATS1-K751 Q,the acetylation mimic mutant potentiated lung cancer cell migration,invasion and tumor growth,whereas LATS1-K751 R,the acetylation deficient mutant inhibited these functions.Taken together,we demonstrated a previously unidentified post-translational modification of LATS1 that converts LATS1 from a tumor suppressor to a tumor promoter by suppression of Hippo signalling through acetylation of LATS1.展开更多
Background:The Nuclear Dbf2-related(NDR1)kinase is a member of the NDR/LATS family,which was a supplementary of Hippo pathway.However,whether NDR1 could inhibit glioblastoma(GBM)growth by phosphorylating Yes-associate...Background:The Nuclear Dbf2-related(NDR1)kinase is a member of the NDR/LATS family,which was a supplementary of Hippo pathway.However,whether NDR1 could inhibit glioblastoma(GBM)growth by phosphorylating Yes-associated protein(YAP)remains unknown.Meanwhile,the role of NDR1 in GBM was not clear.This study aimed to investigate the role of NDR1-YAP pathway in GBM.Methods:Bioinformation analysis and immunohistochemistry(IHC)were performed to identify the expression of NDR1 in GBM.The effect of NDR1 on cell proliferation and cell cycle was analyzed utilizing CCK-8,clone formation,immunofluorescence and flow cytometry,respectively.In addition,the xenograft tumor model was established as well.Protein interaction was examined by Coimmunoprecipitation and immunofluorescence to observe co-localization.Results:Bioinformation analysis and IHC of our patients’tumor tissues showed that expression of NDR1 in tumor tissue was relatively lower than that in normal tissues and was positively related to a lower survival rate.NDR1 could markedly reduce the proliferation and colony formation of U87 and U251.Furthermore,the results of flow cytometry showed that NDR1 led to cell cycle arrest at the G1 phase.Tumor growth was also inhibited in xenograft nude mouse models in NDR1-overexpression group.Western blotting and immunofluorescence showed that NDR1 could integrate with and phosphorylate YAP at S127 site.Meanwhile,NDR1 could mediate apoptosis process.Conclusion:In summary,our findings point out that NDR1 functions as a tumor suppressor in GBM.NDR1 is identified as a novel regulator of YAP,which gives us an in-depth comprehension of the Hippo signaling pathway.展开更多
基金supported by the National Natural Science Foundation of China(81503187)。
文摘Hepatocellular carcinoma(HCC)is one of the common most malignant tumors.This study aimed to determine the in vitro and in vivo anticancer activity of cordycepin and elucidate its mechanism of action.The results of in vitro and in vivo studies revealed that cordycepin inhibited proliferation and migration in HepG-2 cells and inhibited the growth of HepG-2 xenograft-bearing nude mice by inducing apoptosis.Transcriptome sequencing analysis revealed a total of 403 differential genes,which revealed that cordycepin may play an anti-HCC role by regulating Hippo signaling pathway.The regulatory effects of cordycepin on the Hippo signaling pathway was further investigated using a YAP1 inhibitor.The results demonstrated that cordycepin upregulated the expression of MST1 and LAST1,and subsequently inhibited YAP1,which activated the Hippo signaling pathway.This in turn downregulated the expression of GBP3 and ETV5,and subsequently inhibited cell proliferation and migration.Additionally,YAP1 regulated the expression of Bax and Bcl-2,regulated the mitochondrial apoptotic pathway,and induced apoptosis by upregulating the expression of the caspase-3 protein.In summary,this study reveals that cordycepin exerts its anti-hepatocarcinoma effect through regulating Hippo signaling pathway,and GBP3 and ETV5 may be potential therapeutic targets for hepatocarcinoma.
基金supported by the National Natural Science Fund(82004337)the Beijing University of Chinese Medicine new teacher launch fund(2020-JYB-XJSJJ-002)。
文摘Objective:To explore the mechanism of Huatan Sanjie Fang(HTSJ)in regulating goiter in Graves'disease(GD)mice by detecting key factors of the Hippo signaling pathway.Methods:A mouse model of GD was established by injecting Ad-TSHR289 adenovirus into the bilateral quadriceps femoris of female mice.Successful mouse models were then randomly divided into a model group,methimazole(MMI)group,and HTSJ group,and fed with deionized water,MMI(4.5 mg/kg per day),and HTSJ(35.10 g/kg per day),respectively,for 10 weeks.Histopathological changes of the thyroid gland were subsequently observed by hematoxylin-eosin staining.Radioimmunoassay was used to detect serum total thyroxine(T4)and thyrotrophin-receptor antibody(TRAb)levels.The relative expression of mRNA of Mst1,YAP,and TAZ were detected by quantitative real-time polymerase chain reaction,while the protein expression of Mst1,YAP,TAZ,pMst1,and pYAP were detected by western blot.Results:After 10 weeks of drug intervention,goiter and other pathological changes in the HTSJ group significantly improved compared with the model group,and the levels of serum T4 and TRAb significantly decreased(P=.002,P<.001,respectively).Decreased mRNA expression of Mst1,YAP,and TAZ,the key factors of the Hippo signaling transduction pathway,was also observed(P=.002,P=.022,P<.001,respectively).In contrast,protein expression of Mst1(P=.046),pMst1(P=.026),and p YAP(P=.004)increased,while protein expression of YAP and TAZ decreased(P=.041,P<.001,respectively).Conclusion:HTSJ can effectively improve goiter in GD mice through the Hippo signaling pathway.
基金National Natural Science Foundation of China(81573813,81173598)Sichuan Provincial Admin⁃istration of Traditional Chinese Medicine of China(2021MS447)+1 种基金Excellent Talent Program of Chengdu University of Tra⁃ditional Chinese Medicine of China(YXRC2019002,ZRYY1917)and Open Research Fund of the State Key Laboratory of Southwestern Chinese Medicine Resources of China(2020XSGG006)。
文摘OBJECTIVE To investigate the effect of scutellarin on the apoptosis of human colorectal cancer cells via the Hippo signaling pathway in vitro.METHODS MTT colorimetric method was used to detect the influence of scutellarin on the survival rate of HCT116 cells.And the effect of scutellarin at various concentrations on cell morphology was observed by microscopy.Cell scratch experiment was used to detect the influence of scutellarin on the migration of HCT116 cells.Hoechst33342/PI double staining method was used to detect the effect of scutellarin on the apoptosis of HCT116 cells.Western blotting method was used to assess the action of scutellarin on the expressions of Hippo signaling pathway-related proteins Mst1,Lats1,YAP1,p-YAP(Ser127),TAZ,and its downstream effector proteins c-Myc and cyclin D1,as well as apoptosis-related proteins Bcl-2 and Bax in HCT116 cells.RESULTS Scutellarin significantly affected the morphology of HCT116 cells and reduced the survival rate of HCT116 cells.Hoechst33342/PI double staining showed that scutellarin effectively induced the apoptosis of HCT116 cells.Western blotting analysis showed that the expression levels of Hippo signaling pathway-related proteins Mst1,Lats1,YAP1,TAZ and its downstream effector proteins c-Myc,cyclin D1 were down-regulated in a concentration-dependent manner by scutellarin,and the expression of p-YAP(ser127)was up-regulated.Moreover,scutellarin substantially lessened the expression level of apoptosis-related protein Bcl-2,and promoted the protein level of Bax.CONCLUSION Scutellarin may inhibit the proliferation and migration of HCT116 cells,while induce its apoptosis,potentially by activation of Hippo signaling pathway.
基金This work was supported by the Roswell Park Cancer Institute and National Cancer Institute(NCI)Grant#P30 CA016056,Roswell Park Alliance Foundation,the National Cancer Institute(NCI)R01 CA207504 and the American Cancer Society Research Scholar Grant RSG-14-214-01-TBE(to J.Z.).
文摘Regulation of the Hippo signaling pathway is essential for normal organ growth and tissue homeostasis.The proteins that act to regulate this pathway are important for ensuring proper function and cellular location.Deubiquitinases(DUBs)are a family of proteases that act upon many proteins.While ubiquitinases add ubiquitin and target proteins for degradation,DUBs act by removing ubiquitin(Ub)moieties.Changes in ubiquitin chain topology results in the stabilization of proteins,membrane trafficking,and the alteration of cellular localization.While the roles of these proteins have been well established in a cancer setting,their convergence in cancer is still under investigation.In this review,we discuss the roles that DUBs play in the regulation of the Hippo signaling pathway for homeostasis and disease.
基金This work was supported by grants from the National Nature Science Foundation of China(32170862,31872845)Major Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defect in Hunan Province(2019SK1012)+4 种基金Key Grant of Research and Development in Hunan Province(2020DK2002)High-Level Talent Gathering Project in Hunan Province(2018RS3066)Natural Science Foundation of Hunan Province(2020JJ5383,2021JJ40365)Health Commission Foundation of Hunan Province(202104052273,202102050927)Hunan Province College Student Research Learning and Innovative Experiment Project(S202010542084).
文摘Yes-associated protein 1(YAP1)is a downstream effector of the Hippo signaling pathway,and it is involved in tumorigenesis,tissue repair,growth,and development.In this review,the biological roles and the mechanisms of YAP1 in mediating stem cell fate decisions are discussed,including cell proliferation,differentiation,and apoptosis.In general,YAP1 promotes the proliferation and differentiation of stem cells,including embryonic stem cells and adult stem cells.It inhibits apoptosis by binding to the transcription factors,e.g.,transcriptional enhanced associate domain(TEAD),Smad,runt-related transcription factor 1/2,p73,p63,and Erb84,to maintain tissue homeostasis.The translocalization of YAP1 in cellular nuclei and the phosphorylation in the cytoplasm work as important and unusual events for the activation of YAP1.Moreover,YAP1 serves as the crosstalk for the Hippo pathway and other signaling pathways,including the Wnt and Notch pathways.It is highlighted in this review that YAP1 is an essential regulator for stem cells that have significant applications in regenerative medicine and reproductive medicine.
文摘Polycystic ovary syndrome (PCOS) is a heterogeneous reproductive disease that can cause infertility. The Hippo signaling pathway, a network highly conserved throughout evolution, maintains the balance between follicle proliferation and dormancy. Dynamic changes in primordial follicles cannot occur without the participation of biological signals and mechanical force;however, little is known about the mechanism by which biomechanical signaling triggers PCOS, especially in the context of primordial follicle development. To investigate the contribution of mechanical stress and the Hippo signaling pathway to the onset of PCOS, we searched the literature via the PubMed database, and inclusion and exclusion criteria were established to ensure the rigor of this research. We eventually included 54 publications in which Hippo signaling and mechanical force were suggested to play a vital role in the development of primordial follicles as well as elucidate the pathogenesis of PCOS. The Hippo pathway modulating follicle growth can be perturbed via extracellular mechanical stress caused by the stiff ovarian cortical environment in PCOS. Clinical intervention targeting the Hippo pathway can alter the activity of core Hippo members, such as the Yes-associated protein/transcriptional co-activator PDZ-binding motif complex. In some patients with PCOS, follicle overactivation can be attributed to the dysfunction of Hippo signal transduction. PCOS, a condition with various patterns, cannot be accurately explained by a single, specific mechanism. The present review identifies potential targets and therapeutic strategies for PCOS.
基金supported by the National Natural Science Foundation of China(81730071,81972616,81230051,81472734,31170711 and 81773199)the Ministry of Science and Technology of China(2016YFC1302103 and 2015CB553906)+1 种基金Beijing Natural Science Foundation(7120002 and 7171005)Peking University(BMU2018JC004,BMU20120314 and BMU20130364)。
文摘Large tumor suppressor 1(LATS1)is the key kinase controlling activation of Hippo signalling pathway.Post-translational modifications of LATS1 modulate its kinase activity.However,detailed mechanism underlying LATS1 stability and activation remains elusive.Here we report that LATS1 is acetylated by acetyltransferase CBP at K751 and is deacetylated by deacetylases SIRT3 and SIRT4.Acetylation at K751 stabilized LATS1 by decreasing LATS1 ubiquitination and inhibited LATS1 activation by reducing its phosphorylation.Mechanistically,LATS1 acetylation resulted in inhibition of YAP phosphorylation and degradation,leading to increased YAP nucleus translocation and promoted target gene expression.Functionally,LATS1-K751 Q,the acetylation mimic mutant potentiated lung cancer cell migration,invasion and tumor growth,whereas LATS1-K751 R,the acetylation deficient mutant inhibited these functions.Taken together,we demonstrated a previously unidentified post-translational modification of LATS1 that converts LATS1 from a tumor suppressor to a tumor promoter by suppression of Hippo signalling through acetylation of LATS1.
基金This study was supported by a grant from the Capital Clinical Characteristic Application Research Project initiated by Beijing Science and Technology Commission(No.B70489-01).
文摘Background:The Nuclear Dbf2-related(NDR1)kinase is a member of the NDR/LATS family,which was a supplementary of Hippo pathway.However,whether NDR1 could inhibit glioblastoma(GBM)growth by phosphorylating Yes-associated protein(YAP)remains unknown.Meanwhile,the role of NDR1 in GBM was not clear.This study aimed to investigate the role of NDR1-YAP pathway in GBM.Methods:Bioinformation analysis and immunohistochemistry(IHC)were performed to identify the expression of NDR1 in GBM.The effect of NDR1 on cell proliferation and cell cycle was analyzed utilizing CCK-8,clone formation,immunofluorescence and flow cytometry,respectively.In addition,the xenograft tumor model was established as well.Protein interaction was examined by Coimmunoprecipitation and immunofluorescence to observe co-localization.Results:Bioinformation analysis and IHC of our patients’tumor tissues showed that expression of NDR1 in tumor tissue was relatively lower than that in normal tissues and was positively related to a lower survival rate.NDR1 could markedly reduce the proliferation and colony formation of U87 and U251.Furthermore,the results of flow cytometry showed that NDR1 led to cell cycle arrest at the G1 phase.Tumor growth was also inhibited in xenograft nude mouse models in NDR1-overexpression group.Western blotting and immunofluorescence showed that NDR1 could integrate with and phosphorylate YAP at S127 site.Meanwhile,NDR1 could mediate apoptosis process.Conclusion:In summary,our findings point out that NDR1 functions as a tumor suppressor in GBM.NDR1 is identified as a novel regulator of YAP,which gives us an in-depth comprehension of the Hippo signaling pathway.
