The lncRNA HOTAIR is a well-known scaffold for two key epigenetic regulators: the PRC2 member EZH2, responsible of the main repressive H3K27 chromatin mark, and LSD1, able to selectively catalyze the removal of mono- and dimethylated groups from H3K4 and H3K9 (with H3K4 trimethylation generally associated with gene activation and H3K9 dimethylation with gene repression). LSD1 is also responsible of the transcriptional mark H3K36 trimethylation.
HOTAIR acts as an oncogene, overexpressed in several epithelial cancers and strongly correlated to invasion. Furthermore, this lncRNA exerts a key role in the Epithelial-to-Mesenchymal transition (EMT), a transdifferentiation process that is required to metastasis of tumor cells, by allowing migration and invasion. Our recent evidence, indeed, demonstrated that the repressive role of the "master" transcriptional factor Snail, sufficient to induce and maintain EMT, requires the assembly of a HOTAIR/Snail/EZH2 complex on Snail binding sites on the promoters of epithelial genes.
LSD1 function has been previously correlated to EMT regulation. However, while a role in epithelial gene repression has been attributed to this chromatin modifier, its possible function in mesenchymal gene induction is still unexplored. Poorly understood are also whether and how LSD1 contributes to HOTAIR function.
Building on this body of evidence, this project aims to: i) the study of the role of HOTAIR and LSD1 in mesenchymal genes activation in EMT; ii) the identification of LSD1/HOTAIR partners by proteomics approaches and the study of their mechanism of action, specifically focusing on positive regulators of gene expression.
These goals will further clarify the regulatory circuitries in which HOTAIR participates; they will also contribute to the knowledge of how the deregulation of this lncRNA impacts on cancer metastasis.
