The lncRNA HOTAIR: a pleiotropic regulator of epithelial cell plasticity

Abstract

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.

Keywords: Epithelial tumor progression; Epithelial-to-mesenchymal transition (EMT); HOTAIR; Long non-coding RNAs; Metastasis.

Fig. 1

Scheme showing the regulation of HOTAIR expression. (A) The antisense transcription of the HOTAIR gene within the HOXC cluster genes can be controlled by a downstream distal enhancer (HOXC distal enhancer) and an intronic enhancer. The functionally characterized consensus sequences in the promoter region upstream the TSS are listed. (B) HOTAIR levels are post-transcriptionally controlled through the negative regulation by different miRNAs and through the HuR/Ago/let-7-mediated degradation

Fig. 2

Schemes showing the HOTAIR functions in transcriptional regulation of gene expression. HOTAIR scaffolds distinct repressive histone modification activities (i.e. H3K27 trimethylation by EZH2 component of PRC2 complex, H3K4 and H3K9 demethylation and deacetylation by LSD1/CoREST/REST repressor complex). The targeting of this molecular platform to specific loci of the genome, resulting in the EMT induction, can be dependent (A) on the direct formation of triplex helices between the lncRNA and the double stranded DNA target or (B) on the formation of tripartite complexes with specific transcriptional factors (e.g. Snail) that confer site-specificity

Fig. 3

Schemes showing the HOTAIR functions in post-transcriptional regulation of gene expression as a ceRNA in EMT. (A) Endogenous (or EV-delivered) HOTAIR sponges specific miRNAs that target pro-EMT transcripts, thus stabilizing them; (B) in the intercellular communication, HOTAIR ceRNA activity may control the abundance of anti-EMT miRNAs that are specifically sorted and loaded in exosomes, thus promoting EMT in receiving cells

Fig. 4

Schemes showing the HOTAIR functions in post-translational regulation of protein activity. (A) HOTAIR recruits a molecular platform including the E3 ligases Dzip3 and Mex3b. It can facilitate the assembly of Ataxin-1 with Dzip3, as well as of Runx2 with Mex3b, thus promoting ubiquitination and degradation of the transcription inhibitors and EMT-related gene expression (B) HOTAIR regulates MVB transport by controlling the expression and the localization of RAB-GTPase on MVB membrane. Moreover, the lncRNA promotes the docking between V-SNARE and T-SNARE allowing the fusion of MBV and plasma-membrane and the exosome secretion

Fig. 5

HOTAIR targeting approaches. (A) The mutant Hotair-sbid, lacking the domain recruiting EZH2, acts as a competitor of the endogenous HOTAIR for Snail binding, allowing the de-repression of epithelial genes. (B) The small compound AC1NOD4Q (ADQ) specifically binds the 5’ domain of HOTAIR interfering with the interaction between the lncRNA and EZH2 and with the expression of a pro-tumorigenic program of gene expression