MAGEA4 induces growth in normal oral keratinocytes by inhibiting growth arrest and apoptosis

Bhan,Sheetal; Chuang,Alice; Negi,Sandeep S.; Glazer,Chad A.; Califano,Joseph A.

doi:10.3892/or.2012.1934

MAGEA4 induces growth in normal oral keratinocytes by inhibiting growth arrest and apoptosis

Authors:
- Sheetal Bhan
- Alice Chuang
- Sandeep S. Negi
- Chad A. Glazer
- Joseph A. Califano
View Affiliations

Affiliations: Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA, Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
Published online on: July 25, 2012 https://doi.org/10.3892/or.2012.1934
Pages: 1498-1502

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cancer testis antigens (CTAs) are proteins that are normally expressed only in male germ cells and are aberrantly upregulated in a variety of cancers such as melanomas and lung cancer. MAGEA proteins belong to Class I CTAs and are being utilized as targets for cancer immunotherapy. Despite the discovery of the first CTA (MAGEA1) 20 years ago, the functions of these proteins remain poorly understood and evidence suggests both oncogenic as well as tumor suppressive roles for these proteins. Herein, we investigated the role of MAGEA4 in promoting cell growth. When overexpressed, MAGEA4 promotes growth of spontaneously transformed normal oral keratinocytes (NOK-SI). To understand the mechanism of growth stimulation by MAGEA4, we explored the effect of overexpressing MAGEA4 on cell cycle and apoptosis. MAGEA4 inhibits growth arrest of cells in the G1 phase of the cell cycle. We also found that overexpression of MAGEA4 inhibits G418-induced apoptosis of NOK-SI cells. Interestingly, this inhibition was accompanied by repression of two p53 downstream genes, BAX and CDKN1A. Our results indicate that MAGEA4 promotes growth by preventing cell cycle arrest and by inhibiting apoptosis mediated by the p53 transcriptional targets.

View Figures

View References

1	Simpson AJ, Caballero OL, Jungbluth A, Chen YT and Old LJ: Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer. 5:615–625. 2005. View Article : Google Scholar : PubMed/NCBI
2	Zendman AJ, Ruiter DJ and Van Muijen GN: Cancer/testis-associated genes: identification, expression profile, and putative function. J Cell Physiol. 194:272–288. 2003. View Article : Google Scholar : PubMed/NCBI
3	Koslowski M, Bell C, Seitz G, et al: Frequent nonrandom activation of germ-line genes in human cancer. Cancer Res. 64:5988–5993. 2004. View Article : Google Scholar : PubMed/NCBI
4	Caballero OL and Chen YT: Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci. 100:2014–2021. 2009. View Article : Google Scholar : PubMed/NCBI
5	Barker PA and Salehi A: The MAGE proteins: emerging roles in cell cycle progression, apoptosis, and neurogenetic disease. J Neurosci Res. 67:705–712. 2002. View Article : Google Scholar : PubMed/NCBI
6	Sugita M, Geraci M, Gao B, et al: Combined use of oligonucleotide and tissue microarrays identifies cancer/testis antigens as biomarkers in lung carcinoma. Cancer Res. 62:3971–3979. 2002.PubMed/NCBI
7	De Smet C, De Backer O, Faraoni I, Lurquin C, Brasseur F and Boon T: The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc Natl Acad Sci USA. 93:7149–7153. 1996.PubMed/NCBI
8	De Smet C, Lurquin C, Lethe B, Martelange V and Boon T: DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter. Mol Cell Biol. 19:7327–7335. 1999.PubMed/NCBI
9	Weber J, Salgaller M, Samid D, et al: Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2′-deoxycytidine. Cancer Res. 54:1766–1771. 1994.PubMed/NCBI
10	Glazer CA, Smith IM, Ochs MF, et al: Integrative discovery of epigenetically derepressed cancer testis antigens in NSCLC. PloS One. 4:e81892009. View Article : Google Scholar : PubMed/NCBI
11	Smith IM, Glazer CA, Mithani SK, et al: Coordinated activation of candidate proto-oncogenes and cancer testes antigens via promoter demethylation in head and neck cancer and lung cancer. PloS One. 4:e49612009. View Article : Google Scholar : PubMed/NCBI
12	Bhan S, Negi SS, Shao C, et al: BORIS binding to the promoters of cancer testis antigens, MAGEA2, MAGEA3, and MAGEA4, is associated with their transcriptional activation in lung cancer. Clin Cancer Res. 17:4267–4276. 2011. View Article : Google Scholar : PubMed/NCBI
13	Vatolin S, Abdullaev Z, Pack SD, et al: Conditional expression of the CTCF-paralogous transcriptional factor BORIS in normal cells results in demethylation and derepression of MAGE-A1 and reactivation of other cancer-testis genes. Cancer Res. 65:7751–7762. 2005.
14	Hong JA, Kang Y, Abdullaev Z, et al: Reciprocal binding of CTCF and BORIS to the NY-ESO-1 promoter coincides with derepression of this cancer-testis gene in lung cancer cells. Cancer Res. 65:7763–7774. 2005.PubMed/NCBI
15	Scanlan MJ, Gure AO, Jungbluth AA, Old LJ and Chen YT: Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev. 188:22–32. 2002. View Article : Google Scholar : PubMed/NCBI
16	Ghafouri-Fard S and Modarressi MH: Cancer-testis antigens: potential targets for cancer immunotherapy. Arch Iran Med. 12:395–404. 2009.PubMed/NCBI
17	Morishima N, Nakanishi K, Takenouchi H, Shibata T and Yasuhiko Y: An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem. 277:34287–34294. 2002. View Article : Google Scholar : PubMed/NCBI
18	Monte M, Simonatto M, Peche LY, et al: MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents. Proc Natl Acad Sci USA. 103:11160–11165. 2006. View Article : Google Scholar
19	Yang B, O’Herrin S, Wu J, Reagan-Shaw S, Ma Y, Nihal M and Longley BJ: Select cancer testes antigens of the MAGE-A, -B, and -C families are expressed in mast cell lines and promote cell viability in vitro and in vivo. J Invest Dermatol. 127:267–275. 2007. View Article : Google Scholar : PubMed/NCBI
20	Yang B, O’Herrin SM, Wu J, et al: MAGE-A, mMage-B, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. Cancer Res. 67:9954–9962. 2007. View Article : Google Scholar : PubMed/NCBI
21	Glazer CA, Smith IM, Bhan S, et al: The role of MAGEA2 in head and neck cancer. Arch Otolaryngol Head Neck Surg. 137:286–293. 2011. View Article : Google Scholar : PubMed/NCBI
22	Peikert T, Specks U, Farver C, Erzurum SC and Comhair SA: Melanoma antigen A4 is expressed in non-small cell lung cancers and promotes apoptosis. Cancer Res. 66:4693–4700. 2006. View Article : Google Scholar : PubMed/NCBI
23	Nagao T, Higashitsuji H, Nonoguchi K, et al: MAGE-A4 interacts with the liver oncoprotein gankyrin and suppresses its tumorigenic activity. J Biol Chem. 278:10668–10674. 2003. View Article : Google Scholar : PubMed/NCBI
24	Jin QH, Zhao B and Zhang XJ: Cytochrome c release and endoplasmic reticulum stress are involved in caspase-dependent apoptosis induced by G418. Cell Mol Life Sci. 61:1816–1825. 2004.PubMed/NCBI
25	Kuribayashi K and El Deiry WS: Regulation of programmed cell death by the p53 pathway. Adv Exp Med Biol. 615:201–221. 2008. View Article : Google Scholar : PubMed/NCBI
26	Lincet H, Poulain L, Remy JS, Deslandes E, Duigou F, Gauduchon P and Staedel C: The p21(cip1/waf1) cyclin-dependent kinase inhibitor enhances the cytotoxic effect of cisplatin in human ovarian carcinoma cells. Cancer Lett. 161:17–26. 2000. View Article : Google Scholar : PubMed/NCBI