lncRNA HOTAIR functions and therapeutic perspectives.

ABSTRACT

Long non-coding RNAs (lncRNAs) exert central pathophysiological roles through the regulation of gene expression both at transcriptional and post-transcriptional levels. The characterization of lncRNAs' interactome is disclosing several new mechanisms that control disease onset and progression thus opening the way to the development of new pioneering therapeutic approaches. Regarding the lncRNA HOTAIR, found upregulated in several cancers and in liver fibrosis, it has been proved as a potential therapeutic target. HOTAIR acts as a ceRNA for several miRNAs and it directly interacts with chromatin remodelling complexes (e.g. PRC2 and LSD1/NuRD complexes). In this regard, we recently reported the transcription factor SNAIL-mediated recruitment of HOTAIR/PRC2 complex on specific chromatin sites causing epithelial genes' repression through epigenetic chromatin modifications. Conversely, HOTAIR is repressed by the liver-enriched transcriptional factor HNF4a that binds to both HOTAIR promoter and distant enhancer and impairs the formation of a chromatin loop between these genomic regions. In a therapeutic perspective, we design and validated the first example of a dominant negative lncRNA molecule (HOTAIR-sbid) that covers the HOTAIR portion involved in the interaction with SNAIL while is devoid of the domain of interaction with EZH2. Functionally, HOTAIR-sbid expression impairs SNAIL/EZH2/endogenous HOTAIR interaction; thus, PRC2 complex is not recruited on SNAIL-target chromatin sites (i.e. epithelial genes' promoters). Accordingly, the cells rescue an epithelial phenotype, reduce EMT and, in turn, migratory, invasive and anchorage independent growth abilities. This approach promises high level of specificity and limited off-target effects. Future investigations should enhance RNAs' stability and should design strategies for the delivery of these molecules to specific target cells.