Search

Introduction: Cancer-testis antigens (CTAs), including the MAGE protein family, are genes whose expression is typically restricted to the germline, but are aberrantly expressed and presented as antigens in human tumors. Therefore, CTAs constitute excellent targets for cancer immunotherapy. Surprising recent evidence suggests that the aberrant expression of MAGE CTAs in tumors is not simply an inert consequence of widespread genomic deregulation, but rather an important functional event promoting tumorigenesis. Furthermore, the expression of MAGE CTAs correlates with poor prognosis in a variety of cancer types. However, the role of MAGE CTAs as oncogenes driving tumorigenesis has been unexplored and their biochemical activity of MAGEs has been enigmatic. Aims and Methods: In this study, we investigated the function of the large MAGE protein family. First we determined the oncogenic potential of more than 20 MAGE CTAs in 3T3 transformation assays, soft agar anchorage-independent growth assays, and matrigel transwell invasion assays. We then selected several of these oncogenic MAGE CTAs for further in-depth study to identify their biochemical and cellular functions. Using a variety of in vitro and cellular assays, we identified common binding partners of more than ten MAGE proteins, solved the crystal structure of one MAGE protein, and investigated the biochemical activity of several MAGE CTAs. Results and Conclusions: We found that the majority of MAGE CTAs (more than 15) have oncogenic activity in cell transformation, anchorage-independent growth, and/or invasion. Additionally, we showed that a common feature of MAGE proteins is their ability to bind to and enhance the activity of E3 RING ubiquitin ligases, such TRIM28/KAP1, through a conserved tandem winged-helix domain. Importantly, we discovered that several MAGE-TRIM28 ubiquitin ligase complexes directly ubiquitylate and degrade the critical p53 tumor suppressor in vitro and in cancer cells. Thus, our findings clearly establish that MAGE CTAs function as oncogenes through their ability to regulate the activity of E3 RING ubiquitin ligases, resulting in the deregulation of vulnerable signaling pathways (such as the p53 tumor suppressor). These results underscore the importance of MAGE proteins as therapeutic targets for cancer and highlight a novel germline signaling program co-opted by cancer cells to facilitate tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 208. doi:1538-7445.AM2012-208