Melanoma is one of the most worrying tumors due to its high capacity to cause metastasis. Sirt1, a class III histone deacetylase, was shown to be attracted to sites of double strand breaks in DNA, favoring, by recruiting components of the epigenetic machinery, aberrant epigenetic silencing in that region (O’HAGAN et al., 2008). Beyond that, subsequent studies have attributed important roles of Sirt1 and other components of the epigenetic machinery, such as DNA methyltransferases (such as Dnmt3b), in tumor initiation and progression. In this sense, using a murine model of malignant transformation of melanocytes, associated with sustained stress conditions, our goal was to identify genomic sequences differentially associated to Sirt1 and/or Dnmt3B before and after stress condition, represented in our model by anchorage blockade, and analyze if these sequences are targeted by aberrant methylation in cell lines obtained by this process that represent different steps in melanoma progression. We have showed increased DNA damage after 24 hours of anchorage impediment followed by increased Sirt1 expression. In addition, we have showed Sirt1/Dnmt3b association just after this stress condition that leads to malignant transformation. It was identified several DNA sequences differentially associated to Sirt1 and also to Dnmt3b after stress condition which are also associated to genes related to different metabolic processes. Some of these sequences remain associated to Sirt1 and Dnmt3b during melanoma progression, indicating that Dnmt3b remains associated to Sirt1 during malignant transformation. Among the sequences, Tiam1 and Mxd1 are potential targets of Sirt1 and Dnmt3b that have important roles in tumor progression. We have also identified motifs where Sirt1 and Dnmt3b are probably bound before and after stress condition. The main motif related to Sirt1 was coincident with Boris motif. Subsequent analysis are been developed to elucidate the importance of these interesting discoveries. Supported by FAPESP and DAAD.

Citation Format: Fabiana Marcelino Meliso, Camila Tainah da Silva, Simon Coetzee, Thaís Sarraf Sabedot, Houtan Noushmehr, Regine Schneider-Stock, Miriam Galvonas Jasiulionis. DNA sequences differentially associated with Sirt1 and Dnmt3b during melanoma progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4767. doi:10.1158/1538-7445.AM2015-4767

©2015 American Association for Cancer Research.
2015