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Lysine methyltransferase SET is a potential gene target for the treatment of cancer such as hepatocellular carcinoma, human breast cancer and non-small cell lung cancer. SET domain containing 6 (SETD6), as an important member of SET family, has been implicated in promoting cancer cell survival, proliferation and migration in recent years. SETD6 also plays a role in self-renewal of embryonic stem cell to maintain its characteristics. Functions of SETD6 were reported to be related to activation of Wnt/β-catenin pathway and inhibition of NF-κB-mediated inflammatory response by methylations of p21-activated kinase 4 (PAK4) and RelA(P65) respectively. In this review, we would like to give summaries of the roles of SETD6 in cancer development and the corresponding molecular mechanisms, and discuss its application potential as a therapeutic target in cancer.
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Introducción: la curcumina es el principal compuesto polifenólico bioactivo de la planta Curcuma longa. Esta molécula ha mostrado efectos antioxidantes, anti-inflamatorios y anticancerígenos en diferentes modelos experimentales. Como parte de su actividad benéfica en células tumorales, se le ha asociado con la regulación de mecanismos epigenéticos, modulando así diferentes vías de señalización, entre ellas la vía Wnt/ß-catenina, la cual juega un papel fundamental en el desarrollo de cáncer. Objetivos: describir los avances científicos en el estudio de la actividad anti-cancerígena de la curcumina en relación a la modulación de mecanismos epigenéticos y su implicación en la vía Wnt/ß-catenina. Métodos: se realizó una búsqueda sistemática en las bases de datos PubMed, Google Scholar, Scopus y ScienceDirect, utilizando los siguientes criterios de búsqueda: curcumina, epigenética, Wnt/ß-catenina y cáncer. Se incluyeron artículos con importancia científica entre los años 2001-2016, que exploraran la actividad inhibitoria de la curcumina sobre la maquinaria epigenética y/o que evidenciaran un efecto regulador sobre alteraciones en la vía Wnt/ß-catenina. Resultados: se encontró en la literatura una creciente evidencia que involucra a la curcumina con la inhibición de la actividad de enzimas ADN metiltransferasas, acetiltransferasas y desacetilasas de histonas, y por ende en la regulación de alteraciones epigenéticas. Esto lleva a la re-expresión de genes silenciados en diversos tipos de cáncer, lo cual le confiere una actividad antitumoral asociada a la regulación de vías de señalización. En este contexto, se ha demostrado que la curcumina actúa sobre componentes de la vía Wnt/ß-catenina e incluso regula su actividad mediante la desmetilación de antagonistas de Wnt. Conclusiones: este manuscrito discute los potenciales efectos quimiopreventivos de la curcumina asociados con restauración de los mecanismos epigenéticos y la vía de señalización Wnt/ß-catenina(AU)
Introduction: Curcumin is the main bioactive polyphenolic compound in the plant Curcuma longa. This molecule has displayed antioxidant, anti-inflammatory and anti-cancer activity in various experimental models. Its beneficial effect on tumor cells has been associated with the regulation of epigenetic mechanisms, modulating various signaling pathways, among them the Wnt/-catenin pathway, which plays a fundamental role in cancer development. Objectives: Describe the scientific progress achieved in the study of the anti-cancer activity of curcumin in relation to the modulation of epigenetic mechanisms and its implication for the Wnt/?-catenin pathway. Methods: A systematic search was conducted in the databases PubMed, Google Scholar, Scopus and ScienceDirect, using the search terms curcumin, epigenetics, Wnt/?-catenin and cancer. Papers were included which had scientific relevance, had been published between 2001 and 2016, explored the inhibitory activity of curcumin on the epigenetic machinery and/or presented evidence of a regulatory effect on alterations in the Wnt/?-catenin pathway. Results: Growing evidence was found in the literature associating curcumin with inhibition of the activity of the enzymes histone deacetylases, acetyltransferases and DNA methyltransferases, and therefore regulation of epigenetic alterations. This leads to re-expression of silenced genes in various cancer types, granting it antitumor activity associated with the regulation of signaling pathways. In this context, it has been proved that curcumin acts upon components of the Wnt/?-catenin pathway and even regulates their activity through demethylation of Wnt antagonists. Conclusions: The paper discusses the potential chemopreventive effects of curcumin associated with restoration of epigenetic mechanisms and the Wnt/-catenin signaling pathway(AU)
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Humanos , Curcumina/uso terapéutico , Epigenómica , Antineoplásicos Fitogénicos/uso terapéuticoRESUMEN
Objective To elucidate the role of the Wnt/-catenin signaling pathway in regulating the phenotypic transformation of aortic valvular myofibroblasts to osteoblast-like cells.Methods Cultured primary valvular myofibroblastes isolated from porcine aortic valve leaflets were treated with oxidized low-density lipoprotein (ox-LDL) for different lengths of time:24 h,48 h and 72 h.The Wnt signaling pathway inhibitor Dickkopf-1 (DDK-1) was co-incubated with ox-LDL for 72 h.After cells harvest,the expression of myofibroblastic or osteoblast-like phenotype related markers,a-smooth muscle actin (α-SMA),bone morphogenetic protein 2 (BMP2),alkaline phosphatase (ALP) and corebinding factora-1 (Cbfα 1),was detected by Western blotting.The expression and sub cellular localization of β3-catenin was assessed by immunocytochemistry.Changes of the Wnt/β-catenin signaling pathway and the transformation of aortic valvular myofibroblast to osteoblast-like cells were monitored.Results BMP2,ALP and Cbfa 1 protein expression was not or barely detectable in the control group.However,after ox-LDL treatment,the expression of α SMA,BMP2,ALP and Cbfa 1 increased significantly (each P＜0.01) in a time-dependent manner (each P＜0.05).Besides,ox-LDL was also able to up-regulate the protein expression of β-catenin in a time-dependent manner (P＜0.05) and promoted its nuclear translocation.After DKK-1 treatment,the protein expression of β3 catenin and osteogenesis related markers was down regulated (P＜0.05).Conclusions The Wnt/β-catenin signaling pathway may play a crucial role in regulating the transformation of aortic valvular myofibroblasts to an osteoblast like phenotype.
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The heart failure (HF) diseaseasome is marked by substantial alteration in networked signaling pathways. Reductionist paradigm HF investigative approaches have focused on the regulation of a single pathway or single pathway components. In support of a more comprehensive systems biology investigative paradigm, rapidly evolving experimental evidence supports extensive regulatory cross-talk between the TGF-superfamily, Wnt/-catenin and Hippo signaling systems in homeostasis, myocardial development and a variety of non-myocardial diseases. After reviewing the basic components and integrated regulation of each of these three pathways, we review landmark studies in diverse conditions and diseases highlighting the likely critical importance of regulatory cross-talk between these three pathways in the HF.
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[Objective]To investigate the effects of Wnt/?-catenin signal pathway on Schwann cells proliferation promoted by pyrroloquinoline quinine (PQQ) and its molecular mechanisms.[Method]Schwann cells were cultured and purified in vitro. The purity was identified by S-100. PQQ of 10 nmol/L and 100 nmol/L were added into culture medium for 24 hours,respectively. Then the morphological changes promoted by PQQ were observed by inverted microscope. The expression of ?-catenin was detected by RT-PCR and Western blot in Schwann cells promoted by PQQ of different concentration for 72 hours.[Result]Morphological change was observed in Schwann cells treated by PQQ of 10 nmol/L and 100 nmol/L. The most obvious morphological changes took place in the Schwann cells treated by 100 nmol/L of PQQ,the RT-PCR and Western blot results showed that PQQ of 1-1000 nmol/L could up-regulate the expression of ?-catenin,especially when Schwann cells was treated by PQQ of 100 nmol/L(P
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Objective To investigate the interaction between HBx protein and ?-catenin for exploring molecular mechanism in HBV-associated hepatocellular carcinoma.Methods Iimmunocytochemistry and Luciferase Assay were used to detect the endocellular location and transcriptional activity of ?-catenin in normal liver cell line L02 infected by Ad-HBx.Results Immunocytochemistry: there was markedly increased expression of ?-catenin in cytoplasm and nucleus.Luciferase Assay: Ad-HBx led to a significant increase of TCF-4-dependent transcription,the TOP count of Ad-GFP and Ad-HBx-GFP was 1.4 fold and 11 fold as compared to the negative control respectively(P
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The Wnt/?-catenin signal transduction pathway is essential for regulating cell proliferation,movement,differentiation and embryo development. Researchers have found that Wnt pathway is an important regulation factor in the early stimulation of the cardiogenesis and contacts closely the several key events during cardiac morphogenesis. The article reviews the recent studies about the relation between cardiac development and Wnt pathway in early embryo.
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Objective:To study the regulatory mechanism of Wnt/?-Catenin passthway-influenced apoptosis of human gastric cancer line SGC-7901 by detecting the expression of ?-Catenin mRNA,Bcl-2mRNA,Caspase-8mRNA and Caspase-3mRNA.Methods:(1) Expressions of ?-Catenin,Bcl-2,Caspase-8 and Caspase-3mRNAs in groups with or without indomethacin induction were detected by RT-PCR.(2) Methyl thiazolyl tetrazolium(MTT) assay was used to measure the anticancer activity of indomethacin.Results:(1)As compared with groups without indomethacin induction,expression of ?-Catenin mRNA and Bcl-2 mRNA were lower,however,increased expression of Caspase-8 and Caspase-3mRNA were found in SGC-7901 cells after treatment with indomethacin.(2) Indomethacin of 50 ?mol/L at 24 h couldn't induce apoptosis of gastric cancer cells.Indomethacin of 50?mol/L at 48 and 72 h and of 100?mol/L and 200?mol/L at 24、48 and 72 h could induce apoptosis of gastric cancer cells in a dose-and time-dependent manner.Conclusion:Gastric cancer cells may be caused by apoptosis inbalance through Wnt/?-Catenin passthway,which activates expression of proto-oncogene Bcl-2 and inhibites expressions of Caspase-8 and Caspase-3.
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Aim To investigate the relationship between the antitumor activity of berberine and the inhibition of Wnt/?-catenin signaling pathway. Methods The antitumor activities of berberine and total alkaloids of Coptis were assessed for their ability to inhibit the proliferation and to induce apopotosis of human colon cancer lines. A well-established Tcf-4 responsive reporter was introduced into human colon cancer lines to test whether berberine and total alkaloids inhibited the ?-catenin/Tcf4 activity in these cancer cells.Results The proliferation of HCT116 and SW480 cells was inhibited substantially within the concentration ranges of 5 to 40 mg?L~(1) of berberine. 72 hours after treament both HCT116 and SW480 cells underwent apparent apopotosis as demonstrated by Hoechst 33258 staining. Total alkaloids of Coptis had similar effects to berberine when comparable concentrations of it with berberine were used.Berberine effectively and specifically inhibited the Tcf4 reporter activity, but not the positive control reporter at the same experimental conditions. Conclusion Our findings suggest that berberine may be mainly responsible for the antitumor activity of total alkaloids of Coptis and this effect may be mediated at least in part by its inhibitory effect on the Wnt/?-catenin signaling pathway, which is aberrantly activated in many types of human cancer.
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Objective:To develop a Wnt-dependent ?-catenin-mediated functional assay system.Methods:To construct a vector,pCMV-bcGFP,which can express the ?-catenin and green fluorescent protein(GFP) fusion protein;transfect HEK293 with the vector,select the cells with G418 and LiCl and establish the stable cell line,293-bc-GFP by cloning.Results:293-bc-GFP stable cell line was developed;the background expression of ?-catenin-GFP fusion protein was detectable at a very low level in the cell line under fluorescent microscope and via Western blotting analysis;however,the fusion protein was showed to significantly increase in the presence of Wnt1 and lithium.Conclusion:Our results showed that the system is regulated by ?-catenin in a Wnt-responsive fasion.Thus,it can be used as a functional reporter to identify potential upstream factors during tumorigenesis,as well as to screen for the potential anti-cancer agents that specifically inhibit ?-catenin signaling in human tumors.
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Objective:To study the regulatory mechanism of Wnt/?-Catenin passageway influenced apoptosis of human gastric cancer line SGC-7901 by detecting the expression of?-Catenin mRNA,Caspase-3 mRNA and bcl-2 mRNA.Methods:(1) Methyl thiazolyl tetrazolium(MTT)assay was used to measure the anticancer activity of indomethaci.(2)Expression of?-Catenin, Caspase-3 mRNA and bcl-2 mRNA in groups of without induced or induced by indomethaci were detected by RT-PCR. Results:Indomethacin of 50?mol/L at 24h couldn't induce apoptosis of gastric cancer cells.Indomethacin of 50?mol/L at 48 and 72h and of 100?mol/L and 200?mol/L at 24,48 and 72h could induce apoptosis of gastric cancer cells in adose- and time-dependent manner;Compared with groups of without induced by indomethaci,expression of?-Catenin mRNA and bcl-2 mRNA were lower,however,increased expression of Caspase-3 mRNA were found in SGC7901 cells after treatment with indomethaci.Conclusion:Apoptosisin inbalance may be caused by activating expression of bcl-2 proto-oncogene protein and inhibiting expression of Caspase-3 protein through Wnt/?-Catenin passageway in human gastric cancer line SGC7901.