Worldwide,metastasis is the leading cause of more than 90%of cancer-related deaths.Currently,no specific therapies effectively impede metastasis.Metastatic processes are controlled by complex regulatory networks and t...Worldwide,metastasis is the leading cause of more than 90%of cancer-related deaths.Currently,no specific therapies effectively impede metastasis.Metastatic processes are controlled by complex regulatory networks and transcriptional hierarchy.Corepressor metastasis-associated protein 3(MTA3)has been confirmed as a novel component of nucleosome remodeling and histone deacetylation(NuRD).Increasing evidence supports the theory that,in the recruitment of transcription factors,coregulators function as master regulators rather than passive passengers.As a master regulator,MTA3 governs the target selection for Nu RD and functions as a transcriptional repressor.MTA3dysregulation is associated with tumor progression,invasion,and metastasis in various cancers.MTA3 is also a key regulator of E-cadherin expression and epithelial-to-mesenchymal transition.Elucidating the functions of MTA3 might help to find additional therapeutic approaches for targeting components of NuRD.展开更多
Background:Steroid receptor-associated and regulated protein(SRARP)suppresses tumor progression and modulates steroid receptor signaling by interacting with estrogen receptors and androgen receptors in breast cancer.I...Background:Steroid receptor-associated and regulated protein(SRARP)suppresses tumor progression and modulates steroid receptor signaling by interacting with estrogen receptors and androgen receptors in breast cancer.In endometrial cancer(EC),progesterone receptor(PR)signaling is crucial for responsiveness to progestin therapy.The aim of this study was to investigate the role of SRARP in tumor progression and PR signaling in EC.Methods:Ribonucleic acid sequencing data from the Cancer Genome Atlas,Clinical Proteomic Tumor Analysis Consortium,and Gene Expression Omnibus were used to analyze the clinical significance of SRARP and its correlation with PR expression in EC.The correlation between SRARP and PR expression was validated in EC samples obtained from Peking University People’s Hospital.SRARP function was investigated by lentivirus-mediated overexpression in Ishikawa and HEC-50B cells.Cell Counting Kit-8 assays,cell cycle analyses,wound healing assays,and Transwell assays were used to evaluate cell proliferation,migration,and invasion.Western blotting and quantitative real-time polymerase chain reaction were used to evaluate gene expression.The effects of SRARP on the regulation of PR signaling were determined by co-immunoprecipitation,PR response element(PRE)luciferase reporter assay,and PR downstream gene detection.Results:Higher SRARP expression was significantly associated with better overall survival and disease-free survival and less aggressive EC types.SRARP overexpression suppressed growth,migration,and invasion in EC cells,increased E-cadherin expression,and decreased N-cadherin and Wnt family member 7A(WNT7A)expression.SRARP expression was positively correlated with PR expression in EC tissues.In SRARP-overexpressing cells,PR isoform B(PRB)was upregulated and SRARP bound to PRB.Significant increases in PRE-based luciferase activity and expression levels of PR target genes were observed in response to medroxyprogesterone acetate.Conclusions:This study illustrates that SRARP exerts a tumor-suppressiv展开更多
Prostate cancer(PCa)progression relies on androgen receptor(AR)action.Preventing AR’s ligand-activation is the frontline treatment for metastatic PCa.Androgen deprivation therapy(ADT)that inhibits AR ligand-binding i...Prostate cancer(PCa)progression relies on androgen receptor(AR)action.Preventing AR’s ligand-activation is the frontline treatment for metastatic PCa.Androgen deprivation therapy(ADT)that inhibits AR ligand-binding initially induces remission but eventually fails,mainly because of adaptive PCa responses that restore AR action.The vast majority of castration-resistant PCa(CRPC)continues to rely on AR activity.Novel therapeutic strategies are being explored that involve targeting other critical AR domains such as those that mediate its constitutively active transactivation function,its DNA binding ability,or its interaction with co-operating transcriptional regulators.Considerable molecular and clinical variability has been found in AR’s interaction with its ligands,DNA binding motifs,and its associated coregulators and transcription factors.Here,we review evidence that each of these levels of AR regulation can individually and differentially impact transcription by AR.In addition,we examine emerging insights suggesting that each can also impact the other,and that all three may collaborate to induce gene-specific AR target gene expression,likely via AR allosteric effects.For the purpose of this review,we refer to the modulating influence of these differential and/or interdependent contributions of ligands,cognate DNA-binding motifs and critical regulatory protein interactions on AR’s transcriptional output,which may influence the efficiency of the novel PCa therapeutic approaches under consideration,as co-regulation of AR activity.展开更多
ARA267-a is a newly identified androgen receptor coactivator. In order to further elucidate its precise role in cells, using the ARA267- a fragment containing four PHD and one SET conserved domains as bait we revealed...ARA267-a is a newly identified androgen receptor coactivator. In order to further elucidate its precise role in cells, using the ARA267- a fragment containing four PHD and one SET conserved domains as bait we revealed an ARA267-a-PHD-SET-interacting protein, death receptor-6 (DR6), in the yeast two-hybrid screening. DR6 is the member of TNF receptor family and has a death domain in its intracellular cytoplasmic portion (DR6cp) to mediate the cell apoptosis. The interaction between ARA267-a-PHD-SET and DR6cp was confirmed in vitro and in vivo. Our finding implied that androgen signaling pathway might cross talk with apoptosis sig-naling pathway through the interaction between ARA267-a and DR6.展开更多
Estrogen exerts its biological effects through two signal pathways,the genomic and non-genomic pathway,both of which contribute to cell homeostasis.The non-genomic pathway has been suggested to be important in estroge...Estrogen exerts its biological effects through two signal pathways,the genomic and non-genomic pathway,both of which contribute to cell homeostasis.The non-genomic pathway has been suggested to be important in estrogen-induced cardio-,neuron-,and osteoprotection,and confers the ability of the cell to rapidly respond to its environment.The effects of the non-genomic pathway are the regulation of different cellular processes,such as proliferation,survival,apoptosis,and other functions in diverse cell-types.The proline-,glutamic acid-,and leucine-rich protein 1(PELP1),is now known as a modulator of the estrogen receptors,and is also a novel coregulator of the non-genomic signal pathway with various functions.Therefore,the evaluation of the molecular crosstalk between PELP1 and the non-genomic pathway may lead to the development of functionally selective estrogen receptor modulators which can participate in the multiple functions of estrogen signaling in reproductive tissues and other organs.展开更多
PIAS(protein inhibitor of activated STAT)蛋白家族能够与许多蛋白质发生相互作用,其中大部分为转录因子。PIASx是4个组成成员中的一种,其包括两个亚型。PIASx通过与不同种类的蛋白相互作用,影响它们的活性和功能。PIASx蛋白的调控机...PIAS(protein inhibitor of activated STAT)蛋白家族能够与许多蛋白质发生相互作用,其中大部分为转录因子。PIASx是4个组成成员中的一种,其包括两个亚型。PIASx通过与不同种类的蛋白相互作用,影响它们的活性和功能。PIASx蛋白的调控机制主要有两种:一种是通过其自身所具有的SUMO(smallubiquitin-related modifiers)E3连接酶活性,促进对一些转录因子、转录辅因子的SUMO化修饰,从而调控它们的转录活性;另一种是作为构架蛋白,通过与雄激素受体的作用参与雄激素介导的基因转录调节。PIAS蛋白的上述两种作用机制并不是完全互相排斥的,这体现了PIASx蛋白功能的特异性和复杂性。展开更多
Colorectal cancer(CRC) is one of the most common human cancers and the cause of about 700000 deaths per year worldwide. Deregulation of the WNT/β-catenin pathway is a key event in CRC initiation. This pathway interac...Colorectal cancer(CRC) is one of the most common human cancers and the cause of about 700000 deaths per year worldwide. Deregulation of the WNT/β-catenin pathway is a key event in CRC initiation. This pathway interacts with other nuclear signaling pathways, including members of the nuclear receptor superfamily and their transcription coregulators. In this review, we provide an overview of the literature dealing with the main coactivators(NCo A-1 to 3, NCo A-6, PGC1-α, p300, CREBBP and MED1) and corepressors(N-Co R1 and 2, NRIP1 and MTA1) of nuclear receptors and summarize their links with the WNT/β-catenin signaling cascade, their expression in CRC and their role in intestinal physiopathology.展开更多
基金supported in part by the National Natural Science Foundation of China(Nos.81071736,30973508,and 81572876)the Clinical Research Enhancement Initiative of Shantou University Medical College(Nos.201412 and 201421)the Collaborative and Creative Center,Molecular Diagnosis and Personalized Medicine,Shantou University,Guangdong Province,and the Department of Education,Guangdong Government under the Top-tier University Development Scheme for Research and Control of Infectious Diseases(Nos.2015072,2015065,2015020,and 2015077)
文摘Worldwide,metastasis is the leading cause of more than 90%of cancer-related deaths.Currently,no specific therapies effectively impede metastasis.Metastatic processes are controlled by complex regulatory networks and transcriptional hierarchy.Corepressor metastasis-associated protein 3(MTA3)has been confirmed as a novel component of nucleosome remodeling and histone deacetylation(NuRD).Increasing evidence supports the theory that,in the recruitment of transcription factors,coregulators function as master regulators rather than passive passengers.As a master regulator,MTA3 governs the target selection for Nu RD and functions as a transcriptional repressor.MTA3dysregulation is associated with tumor progression,invasion,and metastasis in various cancers.MTA3 is also a key regulator of E-cadherin expression and epithelial-to-mesenchymal transition.Elucidating the functions of MTA3 might help to find additional therapeutic approaches for targeting components of NuRD.
基金supported by grants from the National Key Technology R&D Program of China(Nos.2019YFC1005200 and 2019YFC1005201).
文摘Background:Steroid receptor-associated and regulated protein(SRARP)suppresses tumor progression and modulates steroid receptor signaling by interacting with estrogen receptors and androgen receptors in breast cancer.In endometrial cancer(EC),progesterone receptor(PR)signaling is crucial for responsiveness to progestin therapy.The aim of this study was to investigate the role of SRARP in tumor progression and PR signaling in EC.Methods:Ribonucleic acid sequencing data from the Cancer Genome Atlas,Clinical Proteomic Tumor Analysis Consortium,and Gene Expression Omnibus were used to analyze the clinical significance of SRARP and its correlation with PR expression in EC.The correlation between SRARP and PR expression was validated in EC samples obtained from Peking University People’s Hospital.SRARP function was investigated by lentivirus-mediated overexpression in Ishikawa and HEC-50B cells.Cell Counting Kit-8 assays,cell cycle analyses,wound healing assays,and Transwell assays were used to evaluate cell proliferation,migration,and invasion.Western blotting and quantitative real-time polymerase chain reaction were used to evaluate gene expression.The effects of SRARP on the regulation of PR signaling were determined by co-immunoprecipitation,PR response element(PRE)luciferase reporter assay,and PR downstream gene detection.Results:Higher SRARP expression was significantly associated with better overall survival and disease-free survival and less aggressive EC types.SRARP overexpression suppressed growth,migration,and invasion in EC cells,increased E-cadherin expression,and decreased N-cadherin and Wnt family member 7A(WNT7A)expression.SRARP expression was positively correlated with PR expression in EC tissues.In SRARP-overexpressing cells,PR isoform B(PRB)was upregulated and SRARP bound to PRB.Significant increases in PRE-based luciferase activity and expression levels of PR target genes were observed in response to medroxyprogesterone acetate.Conclusions:This study illustrates that SRARP exerts a tumor-suppressiv
基金supported by DOD PCRP award W81XWH-16-1-0404(HVH)NIH NCI grant CA166440(HVH).
文摘Prostate cancer(PCa)progression relies on androgen receptor(AR)action.Preventing AR’s ligand-activation is the frontline treatment for metastatic PCa.Androgen deprivation therapy(ADT)that inhibits AR ligand-binding initially induces remission but eventually fails,mainly because of adaptive PCa responses that restore AR action.The vast majority of castration-resistant PCa(CRPC)continues to rely on AR activity.Novel therapeutic strategies are being explored that involve targeting other critical AR domains such as those that mediate its constitutively active transactivation function,its DNA binding ability,or its interaction with co-operating transcriptional regulators.Considerable molecular and clinical variability has been found in AR’s interaction with its ligands,DNA binding motifs,and its associated coregulators and transcription factors.Here,we review evidence that each of these levels of AR regulation can individually and differentially impact transcription by AR.In addition,we examine emerging insights suggesting that each can also impact the other,and that all three may collaborate to induce gene-specific AR target gene expression,likely via AR allosteric effects.For the purpose of this review,we refer to the modulating influence of these differential and/or interdependent contributions of ligands,cognate DNA-binding motifs and critical regulatory protein interactions on AR’s transcriptional output,which may influence the efficiency of the novel PCa therapeutic approaches under consideration,as co-regulation of AR activity.
基金This work was supported by National Nature Science Foundation of China(Grant No.30120007)the National Special Fund for“211 Project”of China(Grant No.217).
文摘ARA267-a is a newly identified androgen receptor coactivator. In order to further elucidate its precise role in cells, using the ARA267- a fragment containing four PHD and one SET conserved domains as bait we revealed an ARA267-a-PHD-SET-interacting protein, death receptor-6 (DR6), in the yeast two-hybrid screening. DR6 is the member of TNF receptor family and has a death domain in its intracellular cytoplasmic portion (DR6cp) to mediate the cell apoptosis. The interaction between ARA267-a-PHD-SET and DR6cp was confirmed in vitro and in vivo. Our finding implied that androgen signaling pathway might cross talk with apoptosis sig-naling pathway through the interaction between ARA267-a and DR6.
文摘Estrogen exerts its biological effects through two signal pathways,the genomic and non-genomic pathway,both of which contribute to cell homeostasis.The non-genomic pathway has been suggested to be important in estrogen-induced cardio-,neuron-,and osteoprotection,and confers the ability of the cell to rapidly respond to its environment.The effects of the non-genomic pathway are the regulation of different cellular processes,such as proliferation,survival,apoptosis,and other functions in diverse cell-types.The proline-,glutamic acid-,and leucine-rich protein 1(PELP1),is now known as a modulator of the estrogen receptors,and is also a novel coregulator of the non-genomic signal pathway with various functions.Therefore,the evaluation of the molecular crosstalk between PELP1 and the non-genomic pathway may lead to the development of functionally selective estrogen receptor modulators which can participate in the multiple functions of estrogen signaling in reproductive tissues and other organs.
基金Supported by SIRIC and the PHC-UTIQUE program,No.16G 0805PHC-UTIQUE program,No.16G 0805+1 种基金Tunisian government(Bourse d’alternance)INSERM,Universitéde Montpellier,INCa,SIRIC Montpellier,the Institut régional du Cancer de Montpellier
文摘Colorectal cancer(CRC) is one of the most common human cancers and the cause of about 700000 deaths per year worldwide. Deregulation of the WNT/β-catenin pathway is a key event in CRC initiation. This pathway interacts with other nuclear signaling pathways, including members of the nuclear receptor superfamily and their transcription coregulators. In this review, we provide an overview of the literature dealing with the main coactivators(NCo A-1 to 3, NCo A-6, PGC1-α, p300, CREBBP and MED1) and corepressors(N-Co R1 and 2, NRIP1 and MTA1) of nuclear receptors and summarize their links with the WNT/β-catenin signaling cascade, their expression in CRC and their role in intestinal physiopathology.
