XIST lost induces ovarian cancer stem cells to acquire taxol resistance via a KMT2C-dependent way
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Cancer Cell International Open Access
PRIMARY RESEARCH
XIST lost induces ovarian cancer stem cells to acquire taxol resistance via a KMT2C‑dependent way Ruili Huang* , Lijuan Zhu and Yali Zhang
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. Keywords: LncRNA XIST, KMT2C, Ovarian cancer, Tumor stem cells, Proliferation Background Ovarian cancer is one of the three major malignant tumors in female reproductive organs [1, 2]. The incidence rate is second only to cervical cancer and endometrial cancer, but its mortality rate ranks first among gynecological tumors [3]. Ovarian cancer has become *Correspondence: [email protected] Department of Gynaecology and Obstetrics, The First People’s Hospital of Shangqiu, Henan, No. 292 Kaixuan South Road, 476100 Shangqiu, Henan, People’s Republic of China
a malignant tumor that seriously threatens women’s health and life. Clinically, although chemotherapy has a positive effect on tumor control, it is still not clear about improving survival rate and reducing distant metastasis [4]. Therefore, it is particularly necessary to explore new targeted treatments for inhibiting tumor recurrence. In recent years, with the deepening of research on the mechanism of tumorigenesis and development, it has been found that
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