The Cancer/Testis Antigen CAGE with Oncogenic Potential Stimulates Cell Proliferation by Up-regulating Cyclins D1 and E in an AP-1- and E2F-dependent Manner

Abstract

A cancer/testis antigen, CAGE, is widely expressed in various cancer tissues and cancer cell lines but not in normal tissues except the testis. In the present study, ectopic expression of CAGE in fibroblast cells resulted in foci formation, suggesting its cell-transforming ability. Using stable HeLa transfectant clones with the tetracycline-inducible CAGE gene, we found that CAGE overexpression stimulated both anchorage-dependent and -independent cell growth in vitro and promoted tumor growth in a xenograft mouse model. Cell cycle analysis showed that CAGE augments the levels of cyclin D1 and E, thereby activating cyclin-associated cyclin-dependent kinases and subsequently accelerating the G 1 to S progression. Moreover, increased cyclin D1 and E levels in CAGE-overexpressing cells were observed even in a growth arrested state, indicating a direct effect of CAGE on G 1 cyclin expression. CAGE-induced expression of cyclins D1 and E was found to be mediated by AP-1 and E2F-1 transcription factors, and among the AP-1 members, c-Jun and JunD appeared to participate in CAGE-mediated upregulation of cyclin D1. CAGE overexpression also enhanced retinoblastoma phosphorylation and subsequent E2F-1 nuclear translocation. In contrast, small interfering RNA-mediated knockdown of CAGE suppressed the expression of G 1 cyclins, activation of AP-1 and E2F-1, and cell proliferation in both HeLa cervical cancer cells and Malme-3M melanoma cells. These results suggest that the cancer/testis antigen CAGE possesses oncogenic potential and promotes cell cycle progression by inducing AP-1-and E2F-dependent expression of cyclins D1 and E.

The Helicase HAGE Expressed by Malignant Melanoma-Initiating Cells Is Required for Tumor Cell Proliferation in Vivo

“…For instance, p68 (DDX5), p72 (DDX17), and Cancer Associated Antigen (CAGE) (DDX53) have been implicated in promoting cell proliferation and survival in cancer cell lines from different tissue origins (18,(27)(28)(29)(30)(31). Members including Cancer Associated Antigen (CAGE) and HAGE (DDX43) were found to be highly expressed in different cancer tissues and cancer cell lines, suggesting their possible role in tumorigenesis (13,28,(32)(33)(34). In this study, we investigated whether the helicase HAGE (DDX43) could promote ABCB5ϩ MMIC-dependent tumor growth.…”

“…Previous studies have suggested that several RNA helicases, such as DDX1 (9 -10), DDX2 (11), DDX6 (12), and DDX53 (13) play an important role in tumor cell development and proliferation in a variety of cancers. In this study, we looked at the role of HAGE in melanoma cancer initiation and growth associated with malignant melanoma-initiating cells (MMIC) 3 , a subpopulation of chemoresistant cells capable of self-renewal and differentiation and responsible for melanoma tumor initiation, growth, and progression (14).…”

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.…”

Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities

“…The function of the gene is not known, but because it is a member of the DEAD gene family it is likely to be involved in the unwinding of RNA prior to protein synthesis and might very well have a regulatory function. Overexpression of DDX53 has been connected to cell proliferation (17). It has also been suggested that DDX53 confers resistance to anticancer drugs through downregulation of p53 (18), indicating a mechanism in apoptosis.…”