Epigenetic mechanisms of HOX gene modulation in medulloblastoma

Abstract

Over the last 10-15 years, it has been recognized that development is a key for understanding tumor evolution. Many genes that control development are altered in cancer cells and have a role in neoplastic transformation. In this respect, homeobox genes (HOX) are primordial for development and their epigenetic deregulation is being progressively associated with tumor progression in leukemia, breast cancer and others. However, little is known about how Hox genes contribute to the development of medulloblastoma. In medulloblastoma was demonstrated that 3 Hox genes (HoxB3, HoxB4 and HoxC6), MLL-2 and MLL-3 chromatin-modifying proteins are altered; however the mechanisms involved in these deregulations have not been elucidated. In breast cancer was demonstrated the aberrant HOX gene expression together with over-expression of long no coding RNA expression and chromatin remodeling proteins and have a role in cancer metastasis. This led us to raise the hypothesis that epigenetic deregulation of Hox genes may be associated with tumor evolution in medulloblastoma and that these mechanisms involve over-expression of lncRNAs and MLL-2 and MLL-3 proteins. To test this hypothesis two medulloblastoma cell lines (MBs) will be molecularly characterized about lncRNAs from HOX domains which are expressed differentially, the level of Hox genes and MLL-2 and MLL-3 expression levels. Next, it will be generated four cell lines: two cell lines MB/lncRNA+/Luc+ which over-express a specific lncRNA and luciferase gene and two cell lines from medulloblastoma primary cultures or other cell lines with lncRNA knockout by siRNA and expression of luciferase gene. Finally, it will be performed in vitro and in vivo analysis to investigate the role of lncRNA in the modulation of HOX genes and metastatic potential of medulloblastoma. Also, patient samples will be submitted to similar assays to validate the epigenetic mechanisms of HOX genes in primary tumor. (AU)