Carcinogenesis Advance Access originally published online on March 14, 2006
Carcinogenesis 2006 27(9):1758-1767; doi:10.1093/carcin/bgl008
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Plakoglobin is differentially expressed in alveolar and embryonal rhabdomyosarcoma and is regulated by DNA methylation and histone acetylation
Clinica di Oncoematologia Pediatrica, Azienda Ospedaliera-Università di Padova Via Giustiniani 1, 35128 Padova, Italy
1 CEINGE-Centro di Biotecnologie Avanzate, Università Federico II di Napoli Via Comunale Margherita 482, 80145 Napoli, Italy
*To whom correspondence should be addressed at Clinica di Oncoematologia Pediatrica, Azienda Ospedaliera-Università di Padova, via Giustiniani 3, 35128 Padova, Italy. Tel: +39 049 8215678; Fax: +39 049 8213510; Email: angelo.rosolen{at}unipd.it
Plakoglobin (
-catenin) and ß-catenin are pivotal components of cell–cell adherent junctions that link cadherin receptors to the actin cytoskeleton. Whereas ß-catenin overexpression induces cell proliferation and tumor formation, plakoglobin induces tumor suppressor activity. We investigated the expression of plakoglobin in alveolar (ARMS) and embryonal (ERMS) rhabdomyosarcoma (RMS) cell lines and tumors, and found that plakoglobin is present both in the cytoplasm and in the nucleus of ERMS cells, whereas it is absent or detectable at extremely low levels in ARMS. As gene silencing can be mediated by methylation and/or deacetylation of promoter regions, we assessed the effects of the DNA demethylating agent 5-Aza-2'-deoxycytidine (5AzadC) and of the histone deacetylase inhibitor Trichostatin A (TSA), and obtained restoration of plakoglobin expression in ARMS cells cultivated in the presence of 5AzadC and TSA. By methylation-specific PCR, ARMS cells were shown to contain methylated CpG dinucleotides in CpG islands located around the transcriptional start site of one or both alleles, whereas ERMS cells did not. Furthermore, we demonstrated that promoter regions (P1–P3) of plakoglobin gene were associated with hypoacetylated H4 histone in ARMS cells RH4, suggesting that aberrant DNA methylation of the 5' CpG island and histone deacetylation play key roles in silencing the plakoglobin gene. These results demonstrate that plakoglobin is differentially expressed in ARMS and ERMS and that its expression depends on the methylation and acetylation status of the gene.