MAGE-C2 Promotes Growth and Tumorigenicity of Melanoma Cells, Phosphorylation of KAP1, and DNA Damage Repair

Department of Medicine, University of Wisconsin, Carbone Cancer Center, Madison, Wisconsin, USA.
Journal of Investigative Dermatology (Impact Factor: 7.22). 10/2012; 133(3). DOI: 10.1038/jid.2012.355
Source: PubMed


Melanoma-associated antigen-encoding (MAGE) genes are expressed in melanoma and other cancers but not in normal somatic cells. MAGE expression is associated with aggressive tumor growth, poor clinical outcome, and resistance to chemotherapy, but the mechanisms have not been completely elucidated. In this study, we show that downregulation of MAGE-C2 in A375 melanoma cells and low-passage cultures from human metastatic melanomas (MRA cells) results in increased apoptosis and decreased growth of tumor xenografts in athymic nude mice. Previously, we showed that MAGE-C2 binds KAP1, a scaffolding protein that regulates DNA repair. Phosphorylation of KAP1-Serine 824 (Ser824) by ataxia-telangiectasia-mutated (ATM) kinase is necessary for repair of DNA double-strand breaks (DSBs); now we show that MAGE-C2 knockdown reduces, whereas MAGE-C2 overexpression increases, ATM kinase-dependent phosphorylation of KAP1-Ser824. We demonstrate that MAGE-C2 increases co-precipitation of KAP1 with ATM and that binding of MAGE-C2 to KAP1 is necessary for increased KAP1-Ser824 phosphorylation. Furthermore, ectopic expression of MAGE-C2 enhances repair of I-SceI endonuclease-induced DSBs in U-2OS cells. As phosphorylation of KAP1-Ser824 facilitates relaxation of heterochromatin, which is necessary for DNA repair and cellular proliferation, our results suggest that MAGE-C2 can promote tumor growth by phosphorylation of KAP1-Ser824 and by enhancement of DNA damage repair.Journal of Investigative Dermatology advance online publication, 25 October 2012; doi:10.1038/jid.2012.355.

Download full-text


Available from: Imtiaz A Siddiqui, May 28, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cancer-testis antigens belonging to the MAGE family of genes, such as MAGEC2, are commonly and specifically expressed in Multiple Myeloma (MM) and are associated with a more aggressive clinical course and chemotherapy resistance. MAGEC2 is thought to be an excellent candidate for cancer immunotherapy; however, the biological role of MAGEC2 in MM has remained unclear. We investigated the biological role of MAGEC2 in myeloma cells determining the effect of MAGEC2 knockdown on proliferation and apoptosis. Loss of MAGEC2 resulted in reduced proliferation, viability, and anchorage-independent growth of myeloma cells irrespective of the functional status of TP53 (p53). The anti-proliferative effect of MAGEC2 silencing was due to a decrease of cells in the S phase, cell cycle delay at both G0/G1 and/or G2/M, and an increase in the sub-G0/G1 diploid population related to apoptotic cell death. Importantly, overexpression of short hairpin (sh)RNA-refractory MAGEC2 rescued the anti-proliferative effect of mRNA knockdown and protected cells from apoptotic cell death. Our findings support a TP53-independent role of MAGEC2 in promoting the survival of myeloma cells suggesting that MAGEC2-specific immunotherapies have the potential to eradicate the most malignant cells within the myeloma tumour bulk leading to durable clinical responses.
    British Journal of Haematology 07/2012; 48:S101. DOI:10.1016/S0959-8049(12)71098-5 · 4.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ATM, the protein kinase mutated in the rare human disease ataxia telangiectasia (A-T), has been the focus of intense scrutiny over the past two decades. Initially this was because of the unusual radiosensitive phenotype of cells from A-T patients, and latterly because investigating ATM signalling has yielded valuable insights into the DNA damage response, redox signalling and cancer. With the recent explosion in genomic data, ATM alterations have been revealed both in the germline as a predisposing factor for cancer and as somatic changes in tumours themselves. Here we review these findings, as well as advances in the understanding of ATM signalling mechanisms in cancer and ATM inhibition as a strategy for cancer treatment.Oncogene advance online publication, 15 July 2013; doi:10.1038/onc.2013.275.
    Oncogene 07/2013; 33(26). DOI:10.1038/onc.2013.275 · 8.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Blood Cancer Journal is a peer-reviewed, open access online journal publishing pre-clinical and clinical work in the field of hematology with ramifications into translational biology research down to new therapies
    Blood Cancer Journal 05/2014; 4(5):e212. DOI:10.1038/bcj.2014.31 · 3.47 Impact Factor
Show more