The lncRNA HOTAIR: a pleiotropic regulator of epithelial cell plasticity

The epithelial-to-mesenchymal transition (EMT) is a trans-differentiation process that endows epithelial cells with mesenchymal properties, including motility and invasion capacity; therefore, its aberrant reactivation in cancerous cells represents a critical step to gain a metastatic phenotype. The EMT is a dynamic program of cell plasticity; many partial EMT states can be, indeed, encountered and the full inverse mesenchymal-to-epithelial transition (MET) appears fundamental to colonize distant secondary sites. The EMT/MET dynamics is granted by a fine modulation of gene expression in response to intrinsic and extrinsic signals. In this complex scenario, long non-coding RNAs (lncRNAs) emerged as critical players. This review specifically focuses on the lncRNA HOTAIR, as a master regulator of epithelial cell plasticity and EMT in tumors. Molecular mechanisms controlling its expression in differentiated as well as trans-differentiated epithelial cells are highlighted here. Moreover, current knowledge about HOTAIR pleiotropic functions in regulation of both gene expression and protein activities are described. Furthermore, the relevance of the specific HOTAIR targeting and the current challenges of exploiting this lncRNA for therapeutic approaches to counteract the EMT are discussed.

Automated summary

Epithelial-to-mesenchymal transition (EMT) is a cell differentiation process that gives epithelial cells the ability to move and invade, and its abnormal reactivation in cancer cells is crucial for metastasis. EMT is a dynamic program with various states, and the inverse transition, mesenchymal-to-epithelial transition (MET), is important for colonization of distant sites. Long non-coding RNAs (lncRNAs), specifically HOTAIR, play a critical role in regulating epithelial cell plasticity and EMT in tumors. This review focuses on the molecular mechanisms of HOTAIR expression and its functions in gene regulation and protein activities, as well as the challenges of targeting HOTAIR for therapeutic approaches against EMT.