Abstract 4892: Epigenetic reprogramming associated with melanocyte malignant transformation induced by sustained stress condition

Abstract

Abstract Tissue-specific epigenetic patterns are fundamental for an appropriate gene expression control and aberrant epigenetic patterns are invariably seen in cancer, resulting both in oncogene activation and loss of tumor suppressor genes. These genes may have their expression altered by modifications in the promoter epigenetic status and also by epigenetic regulation of miRNAs which may control the expression of the same genes. It has been strongly suggested that epigenetic aberrant patterns could be established early during the carcinogenesis. In this way, epigenetic alterations observed during specific steps of malignant transformation and progression may be useful as tumor detection, diagnosis and prognosis markers. Melanoma is one of the most deadly human cancers, thus urgency needs to exist for the better understand of the regulatory pathways involved in melanocyte malignant transformation and melanoma progression. Results from our laboratory showed that transformed phenotype may be achieved by submitting non-tumorigenic melanocytes (murine melan-a lineage) to sequential cycles of anchorage blockade, which suggests that sustained cell adhesion changes may lead to intracellular alterations with important gene expression impact. This model represents distinct phases of melanoma genesis and seems to be suitable for studying early phases of melanocyte malignant transformation. Both DNA methyltransferases levels and histone marks were found changed throughout this process. In order to gain an improved understanding of the molecular targets of epigenetic machinery along melanoma genesis, we have compared gene expression profiles through oligonucleotide microarray technology (GeneChip® Mouse Genome 430 2.0 Array, Affymetrix Inc.) and miRNA expression profiles through Taqman Low Density Array (Applied Biosystems) of non-tumorigenic melanocytes (melan-a), melanocytes submitted to 4 deadhesion cycles (4C cells), non-metastatic (4C11-) and metastatic melanoma (4C11+), treated or not with DNA demethylating agent (5-Aza-2′-deaxycitidine). The expression of the selected genes was validated by qPCR and ONCOMINE Cancer Microarray Database analysis identified several of these genes differentially expressed in our murine model by altered epigenetic status as aberrantly expressed in human melanomas. This combined analysis reveals epigenetic signatures associated with early phases of melanocyte malignant transformation as well as melanoma progression and may be useful to define new biomarkers associated with different phases of melanoma genesis. Supported by FAPESP (06/61293-1) and CNPq (473139/2009). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4892.