Arginine methylation of SHANK2 by PRMT7 promotes human breast cancer metastasis through activating endosomal FAK signalling.
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ABSTRACT:
SUBMITTER: Liu Y
PROVIDER: S-EPMC7494359 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:MyoD functions as a master regulator to induce muscle-specific gene expression and myogenic differentiation. Here, we demonstrate a positive role of Protein arginine methyltransferase 7 (Prmt7) in MyoD-mediated myoblast differentiation through p38MAPK activation. Prmt7 depletion in primary or C2C12 myoblasts impairs cell cycle withdrawal and myogenic differentiation. Furthermore, Prmt7 depletion decreases the MyoD-reporter activities and the MyoD-mediated myogenic conversion of fibroblasts. Together with MyoD, Prmt7 is recruited to the Myogenin promoter region and Prmt7 depletion attenuates the recruitment of MyoD and its coactivators. The mechanistic study reveals that Prmt7 methylates p38MAPKα at the arginine residue 70, thereby promoting its activation which in turn enhances MyoD activities. The arginine residue 70 to alanine mutation in p38MAPKα impedes MyoD/E47 heterodimerization and the recruitment of Prmt7, MyoD and Baf60c to the Myogenin promoter resulting in blunted Myogenin expression. In conclusion, Prmt7 promotes MyoD-mediated myoblast differentiation through methylation of p38MAPKα at arginine residue 70.
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Project description:BackgroundAs a member of the ERM (ezrin-radixin-moesin) protein family, EZR has been recognized as a regulator of adhesion signal pathways by researchers. Moreover, EZR was thought to play irreplaceable roles in invasion and metastasis of versatile cancers. In this study, we managed to undermine the effect of EZR on proliferation and metastasis in pancreatic cancer (PC).MethodsTo analyze the impact of EZR expression on overall survival and free diseases survival of PC patients, we screened abnormally expressed EZR in PC using the Gene Expression Omnibus database (GEO database) and The Cancer Genome Atlas (TCGA) database. Following, Gene Ontology (GO)-based functional analysis and Gene set enrichment analysis (GSEA) was performed to predicate the possible biological processes in which EZR were involved. The clinicopathological characteristics and prognosis of PC patients were analyzed according to clinical data. Further, immunohistochemistry, western blotting and real time PCR analysis were conducted to analyze the expression level of EZR in PC and paired paracancerous tissues. The effect of EZR on proliferation of PC cell lines were detected by Cell Counting Kit-8 assay, and meanwhile, Transwell assay was performed to detect the effect of EZR on invasion and migration of PC cell.ResultEZR exhibited higher expression level in pancreatic cancer tissues and cell than paracancerous tissues and cell, and its expression level was positively correlated with poor overall survival and diseases-free survival in PC patients. CCK8 assay indicated that EZR facilitated the proliferation of PC cells, meanwhile, Transwell assay showed that EZR promoted the migration and invasion of PC cells. The GO analysis predicated that EZR was involved in biological processes including cell adhesion, ameboidal-type cell migration, cell junction assembly. Through GSEA analysis, pancreatic cancer pathway, and the adhesion junction pathway were screened as the mostly enriched pathways in EZR-regulated pathological process. The inhibition of EZR suppressed proliferation and migration of PC cells. Western blot experiment revealed a positive correlation between EZR and FAK, the proliferation invasion and migration ability of PC cells were significantly decreased after knockdown of EZR.ConclusionOur finding revealed EZR accelerated the progression of PC via FAK/AKT signaling pathway.
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Project description:Histone lysine demethylase 1 (LSD1), the first identified histone demethylase, is overexpressed in multiple tumor types, including breast cancer. However, the mechanisms that cause LSD1 dysregulation in breast cancer remain largely unclear. Here, we report that protein arginine methyltransferase 4 (PRMT4 or CARM1) dimethylates LSD1 at R838, which promotes the binding of the deubiquitinase USP7, resulting in the deubiquitination and stabilization of LSD1. Moreover, CARM1- and USP7- dependent LSD1 stabilization plays a key role in repressing E-cadherin and activating vimentin transcription through promoter H3K4Me2 and H3K9Me2 demethylation, respectively, which promotes invasion and metastasis of breast cancer cells. Consistently, LSD1 arginine methylation levels correlate with tumor grade in human malignant breast carcinoma samples. Our findings unveil a unique mechanism controlling LSD1 stability by arginine methylation, also highlighting the role of the CARM1-USP7-LSD1 axis in breast cancer progression.
| S-SCDT-EMBOR-2019-48597V1 | biostudies-other
Project description:The aryl hydrocarbon receptor nuclear translocator (ARNT) is broadly involved in regulating tumorigenesis by inducing genes that are involved in tumor growth and angiogenesis. Tumorigenesis usually involves normoxic conditions. However, the role of ARNT in tumor metastasis during normoxia remains unclear. Here, we demonstrate that ARNT protein levels were decreased in late-stage human colorectal cancer using immunohistochemical analysis. Down-regulation of ARNT protein promoted cancer cell migration and invasion, which was mediated by activation of the fibronectin/integrin ?1/FAK signaling axis. In addition, the enhancement of migration and invasion in ANRT knockdown cells was blocked when ARNT was restored in the cells. In xenografts in severe combined immunodeficiency mice, tumor growth was significantly inhibited in the ARNT-knockdown condition. However, the tail-vein injection animal model revealed that the depletion of ARNT-induced metastatic lung colonies was further enhanced when ARNT expression was recovered post-injection. Interestingly, chemotherapeutic drugs inhibited ARNT expression and promoted the invasion of residual tumor cells. These results suggest that ARNT may play a positive role during tumor growth (either in early-stage tumor growth or in organ metastases), but plays a negative role in tumor migration and invasion. Therefore, the efficiency of ARNT-targeted therapy during different cancer stages should be carefully evaluated.
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Project description:Hepatocellular carcinoma (HCC) is a malignant tumor with a high metastatic rate. Recent studies have shown that the mitosis‑associated spindle‑assembly checkpoint regulatory protein spindle pole body component 25 homolog (SPC25) promotes HCC progression, although the underlying mechanism has yet to be fully elucidated. The aim of the present study was to investigate the mechanism through which SPC25 may promote HCC progression in greater detail. First, the expression of SPC25 was analyzed in publicly available databases to explore the association between SPC25 and HCC metastasis. Western blotting was subsequently performed to examine the level of SPC25 expression in different HCC cell lines. SPC25 was then silenced in HCCLM3 and Huh7 cells, and the effects of SPC25 silencing were investigated using cell proliferation, wound‑healing, Transwell migration assays and an in vivo mouse model. Finally, the mechanism of SPC25 action with respect to the promotion of HCC metastasis was explored using microarray analysis and rescue experiments. The results obtained demonstrated that SPC25 is highly expressed in HCC, and this high level of expression is associated with poor prognosis and metastasis. Moreover, SPC25 silencing led to a marked inhibition of the invasion and migration of HCC cells both in vitro and in vivo. The gene‑expression profiling and mechanistic experiments suggest that SPC25 preferentially influences the expression of genes associated with extracellular matrix (ECM)‑integrin interactions, including integrin subunit β4 (ITGB4), an upstream element of the integrin pathway. ITGB4 upregulation partly reversed the decline in cell invasion and migration capacities that resulted from SPC25 silencing. Furthermore, deleting both SPC25 and ITGB4 caused a decrease in the phosphorylation of focal adhesion kinase (FAK), phosphoinositide 3‑kinase (PI3K) and AKT, which are downstream elements of the integrin pathway. Taken together, the results of the present study demonstrated the important role of SPC25 as a prognostic indicator and as a promoter of metastasis in HCC, and the underlying mechanism of its action has been partially elucidated, suggesting that SPC25 could be used as a biomarker and as a target for therapeutic intervention in the treatment of HCC.
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Project description:BackgroundCollagens are the most abundant proteins in extra cellular matrix and important components of tumor microenvironment. Recent studies have showed that aberrant expression of collagens can influence tumor cell behaviors. However, their roles in hepatocellular carcinoma (HCC) are poorly understood.MethodsIn this study, we screened all 44 collagen members in HCC using whole transcriptome sequencing data from the public datasets, and collagen type IV alpha1 chain (COL4A1) was identified as most significantly differential expressed gene. Expression of COL4A1 was detected in HCC samples by quantitative real-time polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry (IHC). Finally, functions and potential mechanisms of COL4A1 were explored in HCC progression.ResultsCOL4A1 is the most significantly overexpressed collagen gene in HCC. Upregulation of COL4A1 facilitates the proliferation, migration and invasion of HCC cells through FAK-Src signaling. Expression of COL4A1 is upregulated by RUNX1 in HCC. HCC cells with high COL4A1 expression are sensitive to the treatment with FAK or Src inhibitor.ConclusionCOL4A1 facilitates growth and metastasis in HCC via activation of FAK-Src signaling. High level of COL4A1 may be a potential biomarker for diagnosis and treatment with FAK or Src inhibitor for HCC.
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Project description:Histone lysine demethylase 1 (LSD1), the first identified histone demethylase, is overexpressed in multiple tumor types, including breast cancer. However, the mechanisms that cause LSD1 dysregulation in breast cancer remain largely unclear. Here, we report that protein arginine methyltransferase 4 (PRMT4 or CARM1) dimethylates LSD1 at R838, which promotes the binding of the deubiquitinase USP7, resulting in the deubiquitination and stabilization of LSD1. Moreover, CARM1- and USP7-dependent LSD1 stabilization plays a key role in repressing E-cadherin and activating vimentin transcription through promoter H3K4me2 and H3K9me2 demethylation, respectively, which promotes invasion and metastasis of breast cancer cells. Consistently, LSD1 arginine methylation levels correlate with tumor grade in human malignant breast carcinoma samples. Our findings unveil a unique mechanism controlling LSD1 stability by arginine methylation, also highlighting the role of the CARM1-USP7-LSD1 axis in breast cancer progression.
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Project description:ObjectAt present, there are few effective treatment options available to patients suffering from osteosarcoma (OS). Clarifying the signaling pathways that govern OS oncogenesis may highlight novel approaches to treating this deadly form of cancer. Recent experimental evidence suggests that the transmembrane protein tetraspanin-9 (Tspan9) plays a role in tumor development. This study was thus formulated to assess the molecular role of Tspan9 as a regulator of OS cell metastasis.MethodsGene expression in OS cell lines was evaluated via qRT-PCR, while CCK-8, colony formation, Transwell, and wound healing assays were used to explore the in vitro proliferative, invasive, and migratory activities of OS cells. The relationship between Tspan9 and in vivo OS cell metastasis was assessed by injecting these cells into the tail vein of nude mice. Interactions between the Tspan9 and integrin β1 proteins were explored through mass spectrometric and co-immunoprecipitation, and Western blotting to assess the functional mechanisms whereby Tspan9 shapes OS pathogenesis.ResultsBoth primary OS tumors and OS cell lines commonly exhibited Tspan9 upregulation, and the knockdown of this tetraspanin suppressed the migration, invasion, and epithelial-mesenchymal transition (EMT) activity in OS cells, whereas Tspan9 overexpression resulted in opposite phenotypes. Tumor lung metastasis were significantly impaired in mice implanted with HOS cells in which Tspan9 was downregulated as compared to mice implanted with control HOS cells. Tspan9 was also found to interact with β1 integrin and to contribute to OS metastasis via the amplification of integrin-mediated downstream FAK/Ras/ERK1/2 signaling pathway.ConclusionThese data suggest that Tspan9 can serve as a promising therapeutic target in OS.
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Project description:Thyroid cancer is the most common endocrine malignant disease and the incidence is increasing. DACT2 was found frequently methylated in human lung cancer and hepatocellular carcinoma. To explore the epigenetic change and the role of DACT2 in thyroid cancer, 7 thyroid cancer cell lines, 10 cases of non-cancerous thyroid tissue samples and 99 cases of primary thyroid cancer samples were involved in this study. DACT2 was expressed and unmethylated in K1, SW579, FTC-133, TT, W3 and 8505C cell lines. Loss of expression and complete methylation was found in TPC-1 cells. Restoration of DACT2 expression was induced by 5-aza-2'deoxycytidine treatment. It demonstrates that the expression of DACT2 was regulated by promoter region methylation. In human primary papillary thyroid cancer, 64.6% (64/99) was methylated and methylation of DACT2 was related to lymph node metastasis (p<0.01). Re-expression of DACT2 suppresses cell proliferation, invasion and migration in TPC-1 cells. The activity of TCF/LEF was inhibited by DACT2 in wild-type or mutant β-catenin cells. The activity of TCF/LEF was increased by co-transfecting DACT2 and Dvl2 in wild-type or mutant β-catenin cells. Overexpression of wild-type β-catenin promotes cell migration and invasion in DACT2 stably expressed cells. The expression of β-catenin, c-myc, cyclinD1 and MMP-9 were decreased and the level of phosphorylated β-catenin (p-β-catenin) was increased after restoration of DACT2 expression in TPC-1 cells. The expression of β-catenin, c-myc, cyclinD1 and MMP-9 were increased and the level of p-β-catenin was reduced after knockdown of DACT2 in W3 and SW579 cells. These results suggest that DACT2 suppresses human papillary thyroid cancer growth and metastasis by inhibiting Wnt signaling. In conclusion, DACT2 is frequently methylated in papillary thyroid cancer. DACT2 expression was regulated by promoter region methylation. DACT2 suppresses papillary thyroid cancer proliferation and metastasis by inhibiting Wnt signaling.
| S-EPMC4223043 | biostudies-literature
Project description:BackgroundFocal adhesion plays an essential role in tumour invasiveness and metastasis. Hippo component YAP has been widely reported to be involved in many aspects of tumour biology. However, its role in focal adhesion regulation in breast cancer remains unexplored.MethodsTissue microarray was used to evaluate YAP expression in clinical breast cancer specimens by immunohistochemical staining. Cell migration and invasion abilities were measured by Transwell assay. A cell adhesion assay was used to measure the ability of cell adhesion to gelatin. The focal adhesion was visualized through immunofluorescence. Phosphorylated FAK and other proteins were detected by Western blot analysis. Gene expression profiling was used to screen differently expressed genes, and gene ontology enrichment was performed using DAVID software. The gene mRNA levels were measured by quantitative real-time PCR. The activity of the THBS1-promoter was evaluated by dual luciferase assay. Chromatin immunoprecipitation (ChIP) was used to verify whether YAP could bind to the THBS1-promoter region. The prediction of potential protein-interaction was performed with the String program. The ChIP sequence data of TEAD was obtained from the ENCODE database and analysed via the ChIP-seek tool. The gene expression dataset (GSE30480) of purified tumour cells from primary breast tumour tissues and metastatic lymph nodes was used in the gene set enrichment analysis. Prognostic analysis of the TCGA dataset was performed by the SurvExpress program. Gene expression correlation of the TCGA dataset was analysed via R2: Genomics Analysis and Visualization Platform.ResultsOur study provides evidence that YAP acts as a promoter of focal adhesion and tumour invasiveness via regulating FAK phosphorylation in breast cancer. Further experiments reveal that YAP could induce FAK phosphorylation through a TEAD-dependent manner. Using gene expression profiling and bioinformatics analysis, we identify the FAK upstream gene, thrombospondin 1, as a direct transcriptional target of YAP-TEAD. Silencing THBS1 could reverse the YAP-induced FAK activation and focal adhesion.ConclusionOur results unveil a new signal axis, YAP/THBS1/FAK, in the modulation of cell adhesion and invasiveness, and provides new insights into the crosstalk between Hippo signalling and focal adhesion.
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