HOTAIR lncRNA promotes epithelial–mesenchymal transition by redistributing LSD1 at regulatory chromatin regions

Abstract

Epithelial-to-mesenchymal transition (EMT) describes the loss of epithelial traits and gain of mesenchymal traits by normal cells during development and by neoplastic cells during cancer metastasis. The long noncoding RNA HOTAIR triggers EMT, in part by serving as a scaffold for PRC2 and thus promoting repressive histone H3K27 methylation. In addition to PRC2, HOTAIR interacts with the LSD1 lysine demethylase, an epigenetic regulator of cell fate during development and differentiation, but little is known about the role of LSD1 in HOTAIR function during EMT. Here, we show that HOTAIR requires its LSD1-interacting domain, but not its PRC2-interacting domain, to promote the migration of epithelial cells. This activity is suppressed by LSD1 overexpression. LSD1-HOTAIR interactions induce partial reprogramming of the epithelial transcriptome altering LSD1 distribution at promoter and enhancer regions. Thus, we uncover an unexpected role of HOTAIR in EMT as an LSD1 decommissioning factor, counteracting its activity in the control of epithelial identity.

A single N6-methyladenosine site in lncRNA HOTAIR regulates its function in breast cancer cells

“…While it is evident that m6A modification of A783 in HOTAIR is important for mediating its effects in breast cancer, other m6A sites within HOTAIR appear to play a role in enabling its high expression levels, potentially through transcript stabilization. When we bypass the normal mechanism of chromatin association using a direct tethering approach for HOTAIR (Figure 7A) (Portoso et al, 2017), YTHDC1 is no longer required for chromatin association or stability, yet is required for gene repression, suggesting a direct role in shutting down transcription, perhaps with LSD1 involvement (Jarroux et al, 2021;Tsai et al, 2010). Our work emphasizes the importance of studying the function of individual m6A sites, as each m6A site has the potential to contribute to the function of an RNA in different ways.…”

“…HOTAIR also interacts with lysine-specific demethylase 1 (LSD1), a histone demethylase that acts on H3K4me2, which has been proposed to reinforce repression by HOTAIR(L. Li et al, 2013;Somarowthu et al, 2015;Tsai et al, 2010). A new study in human epithelial kidney cells found that HOTAIR utilizes its LSD1-interacting domain to perturb LSD1 genomic distribution, independent of major changes in H3K4me2, leading to increased invasion (Jarroux et al, 2021). In this context, HOTAIR is proposed to inhibit the normal function of LSD1 in maintaining epithelial cells (Jarroux et al, 2021;McDonald, Wu, Timp, Doi, & Feinberg, 2011;Wang et al, 2009).…”

“…A new study in human epithelial kidney cells found that HOTAIR utilizes its LSD1-interacting domain to perturb LSD1 genomic distribution, independent of major changes in H3K4me2, leading to increased invasion (Jarroux et al, 2021). In this context, HOTAIR is proposed to inhibit the normal function of LSD1 in maintaining epithelial cells (Jarroux et al, 2021;McDonald, Wu, Timp, Doi, & Feinberg, 2011;Wang et al, 2009). In light of these findings, how HOTAIR specifically accomplishes transcriptional repression at its target loci, and how other pathways and cancer contexts influence HOTAIR function, remain elusive.…”

Identification of Epithelial-Mesenchymal Transition- (EMT-) Related LncRNA for Prognostic Prediction and Risk Stratification in Esophageal Squamous Cell Carcinoma

“…Notably, the effect of lncRNA on the epithelial-mesenchymal transition (EMT) of tumor cells has also been confirmed in recent studies [ 15 , 16 ]. EMT is an essential step in the metastasis of malignant tumors, which can transform epithelial-like cells into a mesenchymal-like cell state.…”

Circulating Long Non-Coding RNAs as Novel Potential Biomarkers for Osteogenic Sarcoma

“…Of tens of thousands of metazoan lncRNAs discovered from cDNA libraries and RNAseq data by high throughput transcriptome projects, only a handful of lncRNAs have been functionally characterized. The investigations on this small cohort of lncRNAs have demonstrated that these noncoding transcripts can serve as scaffolds or guides to regulate protein-protein or protein-DNA interactions [28][29][30][31] or can modulate post-translational modification of nonhistone proteins [32]. Moreover, lncRNAs are capable of controlling microRNAs (miRNAs) [33][34][35], and function as enhancers to influence gene transcription, when transcribed from the enhancer regions (enhancer RNA) [36][37][38] or their neighboring loci (noncoding RNA activator) [39,40].…”