Abstract
Copper (Cu) is essential for living organisms, and acts as a cofactor in many metabolic enzymes. To avoid the toxicity of free Cu, organisms have specific transport systems that 'chaperone' the metal to targets. Cancer progression is associated with increased cellular Cu concentrations, whereby proliferative immortality, angiogenesis and metastasis are cancer hallmarks with defined requirements for Cu. The aim of this study is to gather all known Cu-binding proteins and reveal their putative involvement in cancers using the available database resources of RNA transcript levels. Using the database along with manual curation, we identified a total of 54 Cu-binding proteins (named the human Cu proteome). Next, we retrieved RNA expression levels in cancer versus normal tissues from the TCGA database for the human Cu proteome in 18 cancer types, and noted an intricate pattern of up- and downregulation of the genes in different cancers. Hierarchical clustering in combination with bioinformatics and functional genomics analyses allowed for the prediction of cancer-related Cu-binding proteins; these were specifically inspected for the breast cancer data. Finally, for the Cu chaperone ATOX1, which is the only Cu-binding protein proposed to have transcription factor activities, we validated its predicted over-expression in patient breast cancer tissue at the protein level. This collection of Cu-binding proteins, with RNA expression patterns in different cancers, will serve as an excellent resource for mechanistic-molecular studies of Cu-dependent processes in cancer.
Highlights
Metallomics directs Cu to cytoplasmic Cu/Zn superoxide dismutase 1 (SOD1); in the other, Cu is transported to mitochondria by COX17, and with help from additional proteins (i.e., SCOs and COX11), Cu is incorporated into cytochrome c oxidase (COX1 and COX2)
Since Cu is a key component in many essential enzymes,[1,9,10] it is not surprising that Cu is required for at least three characteristic phenomena involved in cancer progression: proliferative immortality, angiogenesis, and metastasis.[11,12]
Based on functional genomics and bioinformatics analysis of the extracted expression level data, we identified Cu-binding proteins that appear important in cancer and, in a proof-of-principle experiment, we confirmed the upregulation of the ATOX1 protein in patient breast cancer tissue
Summary
Metallomics directs Cu to cytoplasmic Cu/Zn superoxide dismutase 1 (SOD1); in the other, Cu is transported to mitochondria by COX17, and with help from additional proteins (i.e., SCOs and COX11), Cu is incorporated into cytochrome c oxidase (COX1 and COX2). Recent unprecedented findings suggest that ATOX1 has transcription factor activities connected to cancer progression.[18] ATOX1 acts as a Cu-dependent transcription factor[19] that promotes the expression of cyclin D1, a key protein involved in the cell cycle and cell proliferation,[20] and the Cu-dependent enzyme SOD3, a major extracellular antioxidant protein and a protectant against hypertension.[21,22] ATOX1 promotes inflammatory neovascularization by acting as a Cu-dependent transcription factor for NADPH oxidase,[23] and is essential for platelet-derived growth factor-induced Cu-dependent cell migration, potentially regulating malignant angiogenesis and vascular remodeling.[24] In some analogy with ATOX1, CCS transports Cu to the nucleus and regulates the formation of the hypoxia-inducible factor 1 (HIF-1) transcriptional complex, which in turn promotes the expression of the vascular endothelial growth factor (VEGF) and, thereby, tumor growth.[25] Our research group recently confirmed the presence of ATOX1 in the nucleus of mammalian cells, but found no binding to the proposed DNA promoter sequence in vitro.[26] from an extensive yeast two hybrid screening, using ATOX1 as a bait, several new human protein partners were detected:[27] interestingly, among the confident hits, several proteins are related to cancer (e.g., CPEB4, DNMT1, and PPM1A that regulate RNA transcription, DNA methylation, and phosphorylation, respectively[28,29,30,31]). Based on functional genomics and bioinformatics analysis of the extracted expression level data, we identified Cu-binding proteins that appear important in cancer and, in a proof-of-principle experiment, we confirmed the upregulation of the ATOX1 protein in patient breast cancer tissue
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