XIST Is a Key Modulator Associated with the Adhesome Network

Abstract

A long non-coding RNA (lncRNA) known as the X-inactivation specific transcript (XIST) plays a central role in X chromosome inactivation - a transcriptional process that silences one of the two X chromosomes in females to ensure dosage compensation between males and females. Much research has been conducted on how XIST regulates X chromosome transcription critical to embryonic development, but recent studies suggest a non-canonical role for XIST in regulating cancer stem cells and cellular plasticity. As cell adhesion and adhesome genes are integral to the regulation of cancer stemness, we explored the previously unrecognized link between XIST and the adhesome network. By performing gene expression and gene ontology analysis on XIST-knockdown ovarian cancer cells, our study showed that XIST loss altered adhesome gene expression and downstream adhesion pathways. Using Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets, we identified distinct correlations between XIST lncRNA and adhesome genes across normal and cancer tissue samples, which are associated with cell stemness. Furthermore, network analysis suggests that XIST may interact with specific adhesome genes within the cell nucleus. This interaction may have significant functional implications, as demonstrated by the hazard ratio analysis of XIST and adhesome gene expression in relation to clinical outcomes. Overall, our results show that among well-annotated functional lncRNAs, XIST appears to be a modulator strongly associated with the adhesome network and cell stemness. Our findings thus support a novel link between lncRNA-mediated epigenetic regulation of cell adhesion genes, highlighting XIST as a key regulator contributing to the adhesome network. Significance StatementThis study identified that XIST, a long non-coding RNA essential for X-chromosome dosage compensation and embryonic development, plays a significant role in modulating the adhesome network. We found that XIST knockdown affected adhesion pathways in ovarian cancer cells, whereas XIST expression is strongly correlated with adhesome gene expression across all tissues. We observed that the interaction between XIST and adhesome genes changes significantly between tumors and normal tissues, and this altered interaction is associated with certain cancer outcomes. These findings reveal a possible link between lncRNA-mediated regulation and adhesome control that is associated with cell stemness signatures and the emergence of cancerous tissues.