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Epigenetic silencing of the lung tumor suppressor cell adhesion molecule 1

 
: Borlak, J.; Buettner, S.M.R.

:

Toxicology letters 258 (2016), Supplement, pp.S92
ISSN: 0378-4274
ISSN: 1879-3169
European Societies of Toxicology (EUROTOX Congress) <52, 2016, Seville>
English
Abstract
Fraunhofer ITEM ()

Abstract
We previously reported the successful isolation and cultivation of spontaneously transformed cell lines from lung tumors of c-Myc & c-Raf transgenic mice. Oncogenomics revealed several tumor suppressors to be significantly repressed and included the cell adhesion molecule 1 (Cadm1) (Reamon-Buettner and Borlak, 2008). Its loss and/or reduction in activity correlate with poor prognosis in lung cancer patients. In pursue of mechanisms the Cadm1 gene regulation was investigated. Analysis of 69 CpGs displayed differential methylation pattern between and within tumor cell lines; apparently the degree of methylation correlated with transcriptional repression. DNA methylation analysis of the Cadm1 promoter revealed core CpGs in the binding sites of Sp1, Sp3 and zinc finger 5 to be hypermethylated, thus averting transcription factor (TF) binding. Alike, treatment of tumor cell lines with mithramycin A, an inhibitor of Sp1/Sp3 binding, resulted in reduction of Cadm1 gene expression to suggest a potential role of Sp1/Sp3 in Cadm1 gene regulation. Conversely, Cadm1 expression was restored by treatment of cell lines with the demethylating agent 5-aza-2′-deoxycytidine. Subsequently performed single-molecule mapping with DNA methyltransferase M.SssI and micrococcal nuclease revealed high nucleosome occupancy and altered positioning (sliding) in silent Cadm1 promoters (Reamon-Buettner and Borlak, 2012). Additionally, chromatin immunoprecipitation of histone variants H2A.Z and H3.3 and H3K4me3 and H3K27me3 evidenced ‘bivalent’ histone modifications. Altogether, the studies highlight the complexity and different possibilities in the transcriptional repression of Cadm1 in lung cancer cells and broaden the perspective in developing epigenetic drugs.

: http://publica.fraunhofer.de/documents/N-467433.html