Defining the human copper proteome and analysis of its expression variation in cancers

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.

Roles of Copper-Binding Proteins in Breast Cancer

“…We recently established the human Cu proteome (i.e., the collection of all identified human Cu-binding proteins) [7]. We revealed a total of 54 proteins and, of these proteins, 12 are classified as Cu transporters (CTR1 and CTR2 for import, CCS and ATOX1 for cytoplasmic transport, and COX11, COX17, SCO1, and SCO2 that provide Cu to the mitochondria).…”

“…For a global view of Cu protein expression changes in various cancers, we recently analyzed the RNA transcript level changes of the Cu proteome (i.e., the identified 54 Cu-binding proteins) in different cancer tissues using information from the Cancer Genome Atlas, or TCGA, database [7]. Many of the proteins in the human Cu proteome exhibit either up- or downregulation in the different cancers [7].…”

“…Many of the proteins in the human Cu proteome exhibit either up- or downregulation in the different cancers [7]. To give some examples, LOX, LOX-like proteins 1 and 2, secreted protein acidic and rich in cysteine (SPARC), and ENOX2 are upregulated in more than 6 out of 18 cancers analyzed.…”

“…To give some examples, LOX, LOX-like proteins 1 and 2, secreted protein acidic and rich in cysteine (SPARC), and ENOX2 are upregulated in more than 6 out of 18 cancers analyzed. With respect to ATOX1, it is upregulated in breast, colorectal, uterus, and liver tumors [7]. Several studies using sources other than TCGA have also assessed transcript levels in different cancers, but these will not be discussed here.…”

“…Our analysis of the TCGA data for breast cancer [7] revealed upregulation of 26% of the Cu proteome proteins: F5, ATP7B, SLC31A1, SCO2, HEPHL1, CUTA, ATOX1, COX17, TYRP1, MT3, LOX-like proteins 1 and 2, SPARC, and MOXD1. With respect to molecular mechanistic studies of Cu proteins’ roles in breast cancer, there is such information reported for ten proteins (described in detail in Table S1) and below we discuss findings for selected proteins of the ten (MEMO1, SPARC, LOX, and some LOX-like proteins), followed by a separate section about ATOX1.…”