XIST lost induces ovarian cancer stem cells to acquire taxol resistance via a KMT2C-dependent way

Abstract

Background/aims: The expression levels of long non-coding RNA XIST are significantly associated with paclitaxel (Pac) sensitivity in ovarian cancer, but the mechanism of action remains unclear. Therefore, this experimental design was based on lncRNA XIST analysis to regulate the effect of XIST on the tumor stem cell and paclitaxel sensitivity in ovarian cancer. Methods: Sphere assay and fluorescence activated cell sorting (FACS) were used to determine the expression levels of XIST and sensitivity to paclitaxel treatment. The effect of the proliferation was detected by MTT assay. Target gene prediction and screening, luciferase reporter assays were used to validate downstream target genes for lncRNA XIS and KMT2C. The expression of KMT2C was detected by RT-qPCR and Western blotting. RT-qPCR was used to detect the expression of cancer stem cell-associated genes SOX2, OCT4 and Nanog. The tumor changes in mice were detected by in vivo experiments in nude mice. Results: There was an inverse correlation between the expression of XIST and cancer stem cell (CD44 + /CD24−) population. XIST promoted methylation of histone H3 methylation at lysine 4 by enhancing the stability of lysine (K)-specific methyltransferase 2C (KMT2C) mRNA. XIST acted on the stability of KMT2C mRNA by directly targeting miR-93-5p. Overexpression of miR-93-5p can reverse the XIST overexpression-induced KMT2C decrease and sphere number increase. Overexpression of KMT2C inhibited XIST silencing-induced proliferation of cancer stem cells, and KMT2C was able to mediate paclitaxel resistance induced by XIST in ovarian cancer. The study found that XIST can affect the expression of KMT2C in the ovarian cancer via targeting miR-93-5p. Conclusion: XIST promoted the sensitivity of ovarian cancer stem cells to paclitaxel in a KMT2C-dependent manner.

Long noncoding RNA XIST: Mechanisms for X chromosome inactivation, roles in sex-biased diseases, and therapeutic opportunities

“… 152 In addition, XIST expression correlates with ovarian cancer development, with downregulation in advanced stages, and higher expression is associated with better prognoses. 152 In ovarian cancer cell lines, XIST overexpression suppresses cell proliferation, 153 , 154 , 155 while XIST knockdown has the opposite effect. 153 XIST suppresses cancer progression through sponging hsa-miR-214-3p 154 and miR-106a.…”

The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells

“…The X-chromosome inactivating specific transcript ( XIST ) gene is localised in the X-chromosome inactivation centre (Xic), encodes for the XIST lncRNA, and is associated with tumour regulation in various malignancies. In ovarian cancer, XIST promotes the stability of lysine (K)-specific methyltransferase 2C (KMT2C) mRNA, thereby indirectly promoting histone H3 methylation at lysine 4 and hence decreasing CSC proliferation [ 145 ]. XIST can also alter the phenotype of CSCs by increasing paclitaxel sensitivity in patients; miR-93-5p can reverse this pathway, demonstrating multifaceted interactions between epigenetics and lncRNAs [ 145 ].…”

“…Several studies have implicated lncRNAs in cancer drug resistance and recent findings showed that lncRNAs can modulate treatment-resistant phenotypes via regulation of CSC biology and function [ 145 , 155 , 156 ].…”

“…In ovarian cancer, XIST promotes the stability of lysine (K)-specific methyltransferase 2C (KMT2C) mRNA, thereby indirectly promoting histone H3 methylation at lysine 4 and hence decreasing CSC proliferation [145]. XIST can also alter the phenotype of CSCs by increasing paclitaxel sensitivity in patients; miR-93-5p can reverse this pathway, demonstrating multifaceted interactions between epigenetics and lncRNAs [145].…”

The Nucleus/Mitochondria-Shuttling LncRNAs Function as New Epigenetic Regulators of Mitophagy in Cancer

“…The expression of HIFs after hypoxia can directly or indirectly stimulate the maintenance of stemness markers, such as OCT4, SOX2, etc ( Zaarour et al, 2021 ). LncRNA XIST can increase the sensitivity of breast CSCs to chemotherapy drugs by regulating KMT2C ( Huang et al, 2020 ). In liver cancer, lncRNA HDAC2 promotes the proliferation and self-renewal of liver CSCs by activating the Hedgehog signaling pathway ( Wu J. et al, 2019 ).…”