A novel RNA-based approach to counteract EMT

Abstract

Epithelial to mesenchymal transition (EMT) is a key signature in both physiological processes (i.e. development, regeneration, wound healing) and in tumor metastasis [1]. While the involvement of transcription factors (e.g. SNAIL, SLUG, ZEB1/2, TWIST1/2) has been extensively explored, the contribution of epigenetic mechanisms has emerged only in the last decades [2]; furthermore, interest is growing in the role of ncRNAs (e.g. miRNAs and lncRNAs) in modulating cell plasticity. In particular, it was reported that HOTAIR, a well-established predictor of metastasis in different solid tumors, is involved in chromatin modification, acting as a scaffold for the general chromatin modifier PRC2 complex in tumorigenesis [3, 4]; however, the mechanisms conferring specificity to the PRC2 recruitment to genomic loci during EMT was not disclosed. In the last years, we focused on the role of the lncRNA HOTAIR in relation to the EMT master transcriptional factor SNAIL. We reported that SNAIL directly interacts with HOTAIR, thus conferring the site-specificity to the recruitment of PRC2 complex on promoters of epithelial genes upon EMT induction [5]. The central mechanistic role of HOTAIR is represented by its bridging activity that allows the interaction between SNAIL and the catalytic subunit of the PRC2 complex, EZH2. Functionally, HOTAIR depletion was shown to inhibit the SNAIL repressive capacity. Building on this evidence, we designed an RNAbased dominant negative molecular approach to counteract HOTAIR function in hepatocellular carcinoma (HCC) cells. RNA therapeutics represent a growing field of investigation and application. The use of RNA molecules shows several advantages since they show a very low immunogenicity, are able to penetrate the cell/nuclear membrane, and to target the desired gene even if highly expressed, they are cheap and easy to synthesize, and can be chemically modified, in order to increase their stability or to stabilize secondary structures. Moreover, concerning the delivery of these molecules, in recent years, many strategies have been developed for increasing the efficient delivery of RNA therapeutic molecules to specific target cells. Some of these strategies are represented by the use Research Perspective