title: Melanoma-associated cancer-testis antigen 16 (CT16) regulates the expression of apoptotic and antiapoptotic genes and promotes cell survival.
abstract: Cancer-testis (CT) antigens are predominantly expressed in testis or placenta, but absent in most adult tissues. During malignant transformation CT genes are often activated. CT antigen 16 (CT16, PAGE5) is frequently expressed in advanced melanoma but its biological function has been unknown. To examine the role of CT16 in cell survival we knocked it down in A2058 melanoma cells using specific siRNAs and exposed the cells to cancer drug cisplatin known to induce apoptosis. As a result, cell survival was markedly decreased. To study the effects of CT16 on cell survival in more detail, the cellular gene expression profiles were investigated after CT16 silencing in CT16 positive A2058 melanoma cells, as well as after CT16 overexpression in CT16 negative WM-266-4 melanoma cells. Among the 11 genes both upregulated by CT16 silencing and downregulated by CT16 overexpression or vice versa, 4 genes were potentially apoptotic or antiapoptotic genes. CT16 was recognized as a positive regulator of antiapoptotic metallothionein 2A and interleukin 8 genes, whereas it inhibited the expression of apoptosis inducing dickkopf 1 (DKK1) gene. In addition CT16 enhanced the expression of fatty acid binding protein 7, a known promoter of melanoma progression. The effect of CT16 on DKK1 expression was p53 independent. Furthermore, CT16 did not regulate apoptotic genes via DNA methylation. In twenty melanoma metastasis tissue samples average DKK1 mRNA level was shown to be significantly (p<0.05) lower in high CT16 expressing tumors (n = 3) when compared to the tumors with low CT16 expression (n = 17). Thus, our results indicate that CT16 promotes the survival of melanoma cells and is therefore a potential target for future drug development.
authors.affiliation: Department of Biochemistry and Food Chemistry, University of Turku, Turku, Finland.
authors.forename: Camilla
authors.initials: C
authors.lastname: Nylund
authors.forename: Pekka
authors.initials: P
authors.lastname: Rappu
authors.forename: Eveliina
authors.initials: E
authors.lastname: Pakula
authors.forename: Aleksi
authors.initials: A
authors.lastname: Heino
authors.forename: Laura
authors.initials: L
authors.lastname: Laato
authors.forename: Laura L
authors.initials: LL
authors.lastname: Elo
authors.forename: Pia
authors.initials: P
authors.lastname: Vihinen
authors.forename: Seppo
authors.initials: S
authors.lastname: Pyrhönen
authors.forename: Gethin R
authors.initials: GR
authors.lastname: Owen
authors.forename: Hannu
authors.initials: H
authors.lastname: Larjava
authors.forename: Markku
authors.initials: M
authors.lastname: Kallajoki
authors.forename: Jyrki
authors.initials: J
authors.lastname: Heino
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D058950:Melanoma-Specific Antigens / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D058950:Melanoma-Specific Antigens; D016159:Tumor Suppressor Protein p53; C558361:melanoma-derived CT16 cancer testis antigen, human