Loss of XIST lncRNA promotes stemness and cellular plasticity in ovarian cancer

Cancer cell plasticity is an emerging hallmark of the disease where cells can transition into different cellular states, contributing to tumor heterogeneity. Cellular plasticity is linked to cancer progression, treatment resistance, and relapse. Cancer Stem Cells (CSCs) play an important role in cancer cell plasticity, and molecular factors contributing to stemness maintenance are still poorly understood. Here, we investigate the role of XIST (X-inactive specific transcript) long noncoding RNA (lncRNA) in ovarian cancer cellular plasticity. We perform in silico and in vitro analyses to better understand its function. Our findings demonstrate a significant downregulation of XIST in ovarian tumors. cancer patients.Tumors with low XIST expression have higher stemness index and decreased overall survival. This reduction is associated with an increased stemness in tumors with XIST index and decreased overall survival rates. XIST knockdown (KD) in ovarian cancer cell lines increases stem cell population. Transcriptomic data show that low XIST expression correlates with the upregulation of the stem cell-specific pathways MYC and MTOR, as well as the metabolic pathway OXPHO. Our study also demonstrates that XIST KD increases specifically mesenchymal cancer stem cell (MCSC) population. Finally, ovarian cancer cells with XIST KD show higher plasticity under hypoxic conditions by transitioning into Epithelial Cancer Stem CellsCell (ECSC). Our data reveal that XIST loss induces CSC enrichment, leading to higher cellular plasticity. These findings highlight the important role of XIST in protecting cell identity in ovarian cancer and open the door to new therapeutic approaches for patients with low XIST expression Overall design: To better understand the function of XIST lncRNA in ovarian cancer, we generate OVCAR3 cell lines that stably express a sgRNA targeting XIST. We also look how OVCAR3 behave in hypoxic enviromnent af XIST knockdown. We generate transcriptomic data by RNA-Sequencing of two diffenrents sgRNA again XIST after and before hypoxic treatment.