Abstract 4263: Dynamic phenotype switching regulated by epigenetic marks along melanoma genesis

Melanoma is the most aggressive form of skin cancer and its incidence is increasing worldwide. Although melanoma is highly curable when early diagnosed, the metastatic melanoma detains the worst prognosis and remains one of the most resistant cancers to treatment. In this light, continuous efforts are made to better understand the pathogenesis of this disease. It has been strongly suggested that aberrant epigenetic events, occurred in specific steps, are important to the establishment and progression of tumor genesis as the occurrence of point genetic mutations. Based on a murine model of malignant transformation, the aim of our group has been identify and understand the effective participation of epigenetic mechanisms in the generation of a transformed phenotype. The study model of melanoma genesis was established in vitro by submitting non-tumorigenic melanocytes (murine melan-a cell line) to sequential cycles of anchorage blockade, proposing that microenvironment interference may lead to intracellular alterations with important gene expression impact. Our cell lines represent distinct phases of melanoma genesis (melan-a melanocytes, 4C pre-malignant melanocytes, 4C11- non-metastatic and 4C11+ metastatic melanoma) and, on an overview, it was observed clearly morphological differences, mainly in intermediate stages of progression, suggesting a transient change from epithelial to mesenchymal phenotype (from melan-a to 4C and 4C11- cell lines) along malignant transformation. This transitory modification was accompanied by a switch in the EMT markers expression, like Snail1 and your targets, β-catenin, E-cadherin and N-cadherin. In parallel, Chd1 (chromatin remodeling factor), Nanog (pluripotency factor) and Jarid1b (histone demethylase) are highly expressed in these intermediate phases (4C and 4C11-), characterizing an open chromatin configuration. Interestingly, expression of most of these genes appear to be controlled by epigenetic mechanisms, both DNA methylation and chromatin modification. We hypothesized that during melanocyte malignant progression associated with sustained stress, an opened chromatin occurrence would facilitate cells to undergo changes in gene expression which allow cell adaptation to new environment and all these alterations are orchestrated by epigenetic events. Supported by FAPESP. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4263. doi:1538-7445.AM2012-4263