Ricerc@Sapienza

Long non-coding (lnc)-RNAs are key signaling molecules controlling cell behavior. Of note, lncRNAs expression is largely deregulated in inherited and acquired disorders, such as cancers. This project focuses on the role of the lncRNA HOTAIR in the Epithelial-to-Mesenchymal transition (EMT), a transdifferentiation process that, allowing invasion of tumor cells in secondary sites, is required to metastasis. HOTAIR is overexpressed in several epithelial cancers and strongly correlated to invasion. Moreover, we have recently provided evidence that this lncRNA exerts a key role in the EMT triggered by the master factor Snail: this transcriptional repressor, sufficient to induce and maintain EMT, must bind to HOTAIR to recruit the Polycomb member EZH2 to specific targets (that will undergo EZH2-induced chromatin repressive modifications). Therefore, Snail-mediated repression of epithelial genes requires HOTAIR.
Building on this evidence, and as a continuation of previous researches, this project aims to: i) the design and the characterization of HOTAIR mutant molecules, potentially acting as dominant negative regulators of HOTAIR function; ii) the identification of HOTAIR partners and the study of their mechanism of action in the chromatin context. The proposed goals will clarify the regulatory circuitries in which HOTAIR participates; they will also define how the deregulation of this lncRNA impacts on cancer.
In gathering this body of evidence, we will acquire knowledge to be applied to successive development of biotechnological tools for innovative lncRNA-based therapeutic strategies in cancer.