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Association between the epigenetic landscape of colorectal cancer cell lines and the treatment response to the demethylating agent Decitabine

Grant number: 12/01476-6
Support type:Scholarships abroad - New Frontiers
Effective date (Start): May 07, 2012
Effective date (End): August 04, 2012
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Raphael Bessa Parmigiani
Grantee:Raphael Bessa Parmigiani
Host: Bing Ren
Home Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil
Local de pesquisa : Ludwig Institute for Cancer Research, San Diego, United States  

Abstract

The recent characterization of the CpG island methylator phenotype (CIMP), observed in 20 to 30 percent of the colorectal cancer samples, confirms the important role of epigenetic mechanisms in the pathogenesis of this tumor type. This phenotype is characterized by the frequent hypermethylation of different regions of the tumor genome. Considering that epigenetic modifications are coordinately modulated, it's reasonable to speculate that besides DNA methylation, the tumors that have such phenotype have also other unique epigenetic alterations (histone modifications and microRNAs expression), which can be involved with tumor biology and evolution, as well as with treatment response. Modulatory drugs of epigenetic mechanisms such as decitabine, a potent DNA-methyltransferase inhibitor, have been tested with relative success on the treatment of different tumor types, including colorectal cancer, even though the underlying molecular mechanisms of its anti-tumoral effects haven't been completely elucidated. The present work aims to characterize the complete epigenetic landscape of colorectal cancer cell lines and its correlation with the response to decitabine treatment. CIMP positive and negative cell lines will be included in this study. Through global analysis approaches, based on next generation sequencing, DNA methylation, histone modifications and microRNAs expression will be analyzed, before and after decitabine treatment. Besides the complete characterization of CIMP, epigenetic alterations induced by decitabine treatment will be evaluated in the different subgroups of cell lines, and also if such alterations can affect their sensitivity to the treatment. (AU)