CircSETDB1 contributes to paclitaxel resistance of ovarian cancer cells by sponging miR-508-3p and regulating ABCC1 expression

Abstract

Ovarian cancer is a gynecological tumor with a poor prognosis. The chemotherapy failure and recurrence induced by paclitaxel (Ptx) resistance are the main reason for the failure of ovarian cancer treatment. In this study, we aimed to explore the role of circular RNA (circRNA) in the regulation of Ptx resistance in ovarian cancer. Quantitative reverse transcription PCR was performed to detect the expression of circRNA SET domain bifurcated histone lysine methyltransferase 1 (circSETDB1), microRNA (miR)-508-3p and ATP-binding cassette subfamily C member 1 (ABCC1) mRNA. The effects of circSETDB1 on Ptx resistance were explored by cell counting kit-8, 5-ethynyl-2′-deoxyuridine, and flow cytometry experiments in vitro. The protein level was assessed by western blot. Dual-luciferase reporter and RNA pull-down assays were carried out to confirm the interactions among circSETDB1, miR-508-3p, and ABCC1. Xenograft tumor experiment was performed to investigate the effect of circSETDB1 on Ptx resistance in vivo. CircSETDB1 was highly expressed in Ptx-resistant ovarian cancer. CircSETDB1 knockdown inhibited cell proliferation viability, half maximal inhibitory concentration value of Ptx, cell cycle progression, and induced cell apoptosis in Ptx-resistant ovarian cancer cells. miR-508-3p was a target of circSETDB1, and inhibition of miR-508-3p overturned the effects of circSETDB1 knockdown on the Ptx resistance of ovarian cancer cells. miR-508-5p could bind to ABCC1. Overexpression of ABCC1 reversed the effects of circSETDB1 knockdown on the Ptx resistance of ovarian cancer cells. CircSETDB1 knockdown also enhanced Ptx sensitivity in vivo. In conclusion, circSETDB1 regulated Ptx resistance of ovarian cancer by targeting miR-508-3p/ABCC1 axis.

circPDK1 competitively binds miR-4731-5p to mediate GIGYF1 expression and increase paclitaxel sensitivity in non-small cell lung cancer

“…Advanced NSCLC patients can benefit from chemotherapy (including PTX) [ 32 ], but efficacy of chemotherapy has been hampered by chemotherapy resistance [ 33 ]. Many circRNAs are involved in the regulation of tumorigenesis and chemotherapy resistance processes [ 34 , 35 ], but the function of most circRNAs remains unclear. This study investigated circPDK1 competitively binding miR-4731-5p in positively regulating GIGYF1 expression in PTX resistance.…”

Drug resistance in ovarian cancer: from mechanism to clinical trial

“…miR-185-5p and miR-326 both target the ABCC1 3'-UTR to regulate the expression of ABCC1 [ 2 ]. miR-508-3p [ 29 ] and miR-134 [ 30 ], which are sponged by CircETDB1 and LINC01118, respectively, can posttranscriptionally regulate the expression of ABCC1. ABCG2 is involved in topotecan resistance in ovarian cancer, which is associated with miR-212-3p downregulation [ 31 ].…”

Circular RNAs in gynecologic cancers: mechanisms and implications for chemotherapy resistance

“…Similarly, circ_0061140 facilitates chromobox 2 (CBX2) expression by binding to miR-136, leading to malignant OC progression and PTX resistance (99). On the other hand, circSETDB1 regulates PTX resistance in OC cells by targeting the miR-508-3p/ABCC1 axis ( Huang et al, 2023 ). In endometrial cancer (EC), circ_0007534 is highly expressed and associated with poor prognosis in EC patients.…”

“…The expression of circSETDB1 was found to be notably higher in PTX-resistant ovarian cancer tissues than in normal tissues. Importantly, OC patients with high circSETDB1 expression had a worse prognosis, according to Kaplan-Meier survival curve analysis ( Huang et al, 2023 ).…”