CT45A1 acts as a new proto-oncogene to trigger tumorigenesis and cancer metastasis

Abstract

Cancer/testis antigen (CTA)-45 family (CT45) belongs to a new family of genes in phylogenetics and is absent in normal tissues except for testis, but is aberrantly overexpressed in various cancer types. Whether CT45 and other CTAs act as proto-oncogenes has not been determined. Using breast cancer as a model, we found that CT45A1, a representative CT45 family member, alone had a weak tumorigenic effect. However, its neoplastic potency was greatly enhanced in the presence of growth factors. Overexpression of CT45A1 in breast cancer cells markedly upregulated various oncogenic and metastatic genes, constitutively activated ERK and CREB signaling pathways, promoted epithelial–mesenchymal transition, and increased cell stemness, tumorigenesis, invasion, and metastasis, whereas silencing CT45A1 significantly reduced cancer cell migration and invasion. We propose that CT45A1 functions as a novel proto-oncogene to trigger oncogenesis and metastasis. CT45A1 and other CT45 members are therefore excellent targets for anticancer drug discovery and targeted tumor therapy, and valuable genes in the study of a molecular phylogenetic tree.

DNA hypomethylation-mediated activation ofCancer/Testis Antigen 45(CT45) genes is associated with disease progression and reduced survival in epithelial ovarian cancer

“…In support of this hypothesis, two recent studies of CT45 provide initial evidence for an oncogenic role for CT45 proteins 23,24 . Koop et al demonstrated that CT45 knockdown in Hodgkin's lymphoma and multiple myeloma cell lines reduced cell adhesion, migration, and invasion 23 .…”

“…CT45 hypomethylation also showed strong correlation with LINE-1 hypomethylation, providing evidence that CT45 expression is linked to the global hypomethylation process that frequently impacts the cancer genome. While this link could be used to argue that CT45 (and more generally CT antigen) gene expression could be a passenger effect, the emerging oncogenic functions of CT antigen genes, including CT45, alternatively suggests that CT antigen gene expression is under positive selection in cancer 23,24,35 . In the case of CT45, recent studies in Hodgkin's disease and breast cancer have established its function in promoting cell migration and invasion, as well as tumor growth and metastasis in vivo 23,24 .…”

“…While this link could be used to argue that CT45 (and more generally CT antigen) gene expression could be a passenger effect, the emerging oncogenic functions of CT antigen genes, including CT45, alternatively suggests that CT antigen gene expression is under positive selection in cancer 23,24,35 . In the case of CT45, recent studies in Hodgkin's disease and breast cancer have established its function in promoting cell migration and invasion, as well as tumor growth and metastasis in vivo 23,24 . The mechanism by which CT45 promotes these activities is not well understood, but may include regulation of the mRNA splicing machinery and/or transcriptional activation of critical pro-oncogenic genes such as TWIST 23,24 .…”

“…Koop et al demonstrated that CT45 knockdown in Hodgkin's lymphoma and multiple myeloma cell lines reduced cell adhesion, migration, and invasion 23 . Shang et al similarly found that CT45A1 overexpression increased migration and invasion, promoted epithelial to mesenchymal transition (EMT), and increased xenograft growth and metastasis, using the MCF7 breast cancer cell line as a model 24 . In both studies, CT45…”

Meiosis-like Functions in Oncogenesis: A New View of Cancer

“…[19][20][21][22][23][24][25][26][27][28][29][30], including the fostering of genome instability, a driver of cancer evolution (24). However, given that the normal function of many CT genes in spermatogenesis is unknown, it remained unclear whether proteins that normally specifically orchestrate meiotic chromosome segregation events (such as interhomolog association/recombination and sister centromere monopolarity) contribute to maintenance and/or development/progression of cancers.…”