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Identification of an enhancer involved in the melanoma-specific expression of the tumor antigen melanotransferrin gene.

ABSTRACT: Melanotransferrin (MTf) is a tumor associated antigen found in abundance on the surface of melanoma cells. It is a transferrin-like protein found in low amount in most adult tissues and whose gene is reminiscent of house-keeping genes. With the goal of understanding the regulatory mechanisms which might explain the enhancement of expression in tumor cells, we report here the characterization of a regulatory element located 2 kbp upstream from the promoter and whose deletion specifically impairs gene expression in melanoma cells; we show that this element is part of an enhancer composed of two modules which are each the target for the AP1 transcription factor. The two modules present a synergistic mode of action specific for melanoma cells which requires both of the 130 bp away AP1 sites. Furthermore, we show that the enhancer behaves differently according to the promoter context.

SUBMITTER: Duchange N

PROVIDER: S-EPMC336932 | biostudies-other | 1992 Jun

REPOSITORIES: biostudies-other

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Identification of an enhancer involved in the melanoma-specific expression of the tumor antigen melanotransferrin gene.

Duchange N N Ochoa A A Plowman G D GD Rozé A A Amdjadi M M Zakin M M MM

Nucleic acids research 19920601 11

Melanotransferrin (MTf) is a tumor associated antigen found in abundance on the surface of melanoma cells. It is a transferrin-like protein found in low amount in most adult tissues and whose gene is reminiscent of house-keeping genes. With the goal of understanding the regulatory mechanisms which might explain the enhancement of expression in tumor cells, we report here the characterization of a regulatory element located 2 kbp upstream from the promoter and whose deletion specifically impairs ...[more]

PMID: 1614870

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Project description:BackgroundMelanoma is the deadliest type of skin cancer. Until now, its pathological mechanisms, particularly the mechanism of metastasis, remain largely unknown. Our study on the identification of genes in association with metastasis for melanoma provides a novel understanding of melanoma.MethodsFrom the Gene Expression Omnibus (GEO) database, the gene expression microarray datasets GSE46517, GSE7553, and GSE8401 were downloaded. We made use of R aiming at analyzing the differentially expressed genes (DEGs) between metastatic and nonmetastatic melanoma. R was also used in differentially expressed miRNA (DEM) data mining from GSE18509, GSE19387, GSE24996, GSE34460, GSE35579, GSE36236, and GSE54492 datasets referring to Li's study. Based on the DEG and DEM data, we performed functional enrichment analysis through the application of the DAVID database. Furthermore, we constructed the protein-protein interaction (PPI) network and established functional modules by making use of the STRING database. Through making use of Cytoscape, the PPI results were visualized. We predicted the targets of the DEMs through applying TargetScan, miRanda, and PITA databases and identified the overlapping genes between DEGs and predicted targets, followed by the construction of DEM-DEG pair network. The expressions of these keratinocyte differentiation-involved genes in Module 1 were identified based on the data from TCGA.Results239 DEGs were screened out in all 3 datasets, which were inclusive of 21 positively regulated genes and 218 negatively regulated genes. Based on these 239 DEGs, we finished constructing the PPI network which was formed from 225 nodes and 846 edges. We finished establishing 3 functional modules. And we analyzed 92 overlapping genes and 26 miRNA, including 11 upregulated genes targeted by 11 negatively regulated DEMs and 81 downregulated genes targeted by 15 positively regulated DEMs. As proof of the differential expression of metastasis-associated genes, eleven keratinocyte differentiation-involved genes, including LOR, EVPL, SPRR1A, FLG, SPRR1B, SPRR2B, TGM1, DSP, CSTA, CDSN, and IVL in Module 1, were obviously downregulated in metastatic melanoma tissue in comparison with primary melanoma tissue based on the data from TCGA.Conclusion239 melanoma metastasis-associated genes and 26 differentially expressed miRNA were identified in our study. The keratinocyte differentiation-involved genes may take part in melanoma metastasis, providing a latent molecular mechanism for this disease.

Project description:BackgroundPSMA expression in the prostate epithelium is controlled by a cis-element, PSMA enhancer (PSME). PSME contains multiple binding sites for Sox proteins, and in this study, we identified Sox7 protein as a negative regulator of PSMA expression through its interaction with PSME.MethodsThe statistical correlation between Sox7 and PSMA mRNA expression was evaluated using five prostate cancer studies from cBioportal. In vitro and in vivo interaction between Sox7 and PSME was evaluated by chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and luciferase reporter assay. Synthetic oligonucleotides were generated to define the sites in PSME that interact with Sox7 protein. Sox7 mutants were generated to identify the region of this protein required to regulate PSMA expression. Sox7 was also stably expressed in LNCaP/C4-2 and 22Rv1 cells to validate the regulation of PSMA expression by Sox7 in vivo.ResultsSox7 mRNA expression negatively correlated with PSMA/FOLH1 and PSMAL/FOLH1B mRNA expression in Broad/Cornell, TCGA and MSKCC studies, but not in two studies containing only metastatic prostate tumors. PC-3 cells mostly expressed the 48.5 KDa isoform 2 of Sox7, and the depletion of this isoform did not restore PSMA expression. Ectopic expression of canonical, wild-type Sox7 in C4-2 and 22Rv1 cells suppressed PSMA protein expression. ChIP assay revealed that canonical Sox7 protein preferentially interacts with PSME in vivo, and EMSA identified the SOX box sites #2 and #4 in PSME as required for its interaction. Sox7 was capable of directly binding to PSME and suppressed PSME-mediated transcription. The NLS regions of Sox7, but not its β-catenin interacting motif, are essential for this suppressing activity. Furthermore, restoration of wild-type Sox7 expression but not Sox7-NLS mutant in Sox7-null prostate cancer cell lines suppressed PSMA expression.ConclusionsThe inactivation of canonical Sox7 is responsible for the upregulated expression of PSMA in non-metastatic prostate cancer.

Dataset Information

Identification of an enhancer involved in the melanoma-specific expression of the tumor antigen melanotransferrin gene.

Publications

Identification of an enhancer involved in the melanoma-specific expression of the tumor antigen melanotransferrin gene.

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