Integrative Analysis of Epigenetic Modulation in Melanoma Cell Response to Decitabine: Clinical Implications

• DOI: 10.1371/journal.pone.0004563
• Publication Date: 2009-02-20T23:35:21Z
• Authors: Ruth Halaban; Michael Krauthammer; Mattia Pelizzola; Elaine Cheng; Daniela Kovacs; Mario Sznol; Stephan Ariyan; Deepak Narayan; Antonella Bacchio...; Annette Molinaro; Yuval Kluger; Min Deng; Nam Tran; Wengeng Zhang; Mauro Picardo; Jan J. Enghild
• Keywords: Decitabine; Epigenetic Therapy

Decitabine, an epigenetic modifier that reactivates genes otherwise suppressed by DNA promoter methylation, is effective for some, but not all cancer patients, especially those with solid tumors. It commonly recognized to overcome resistance and improve outcome, treatment should be guided tumor biology, which includes genotype, epigenotype, gene expression profile. We therefore took integrative approach better understand melanoma cell response clinically relevant dose of decitabine identify complementary targets combined therapy. employed eight different strains, determined their growth, apoptotic damage responses increasing doses decitabine, chose a low, drug perform whole-genome differential expression, bioinformatic analysis, protein validation studies. The data ruled out the response, demonstrated involvement p21Cip1 in p53-independent manner, identified TGFβ pathway CLU TGFBI as markers sensitivity revealed effect on histone modification part decitabine-induced expression. Mutation analysis knockdown siRNA implicated activated β-catenin/MITF, BRAF, NRAS or PTEN mutations source resistance. importance stability predicted from results was validated synergistic Bortezomib, proteasome inhibitor, enhancing growth arrest resistant cells. Our show improved therapy can achieved comprehensive cells, biomarkers patient's selection monitoring well combination