N6-methyladenosine-modified circQKI inhibits prostate cancer docetaxel-sensitivity via miR-188-3p/Beclin-1 pathway

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-04-17 DOI:10.1016/j.lfs.2025.123646

Tong Zhao , Kai Li , Yetao Zhang , Yuxiang Dong , Yongshan Li , Mingyang Pang , Yong Wei , Bing Yao , Qingyi Zhu

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Abstract

Background

Docetaxel (DTX) is used in the first-line chemotherapy for advanced castration-resistant prostate cancer (CRPC), but resistance remains a major clinical challenge. Circular RNAs (circRNAs) play critical roles in DTX resistance. This study aimed to investigate the mechanism of a novel circRNA, circQKI, in DTX resistance and its regulatory network in CRPC.

Methods

DTX-resistant cell lines (PC3/DR and 22RV1/DR) were established, and circQKI's circular structure was validated by Sanger sequencing. CircQKI expression was modulated via siRNA knockdown and overexpression plasmids. Cell viability, apoptosis, and colony formation were assessed by CCK-8, flow cytometry, and clonogenic assays. The interaction between circQKI and miR-188-3p was verified by dual-luciferase reporter, RIP, and RNA pull-down. Autophagy activation was analyzed via Western blot and TEM. Subcutaneous xenograft models evaluated in vivo drug resistance. M6A modification was investigated through m6A RIP-PCR, METTL3/IGF2BP2 knockdown, and stability assays.

Results

CircQKI was significantly upregulated in resistant cells and promoted DTX resistance by sponging miR-188-3p, thereby enhancing Beclin-1 expression and autophagy activation. Inhibiting Beclin-1 or co-treatment with chloroquine (CQ) partially restored DTX sensitivity. Mechanistically, METTL3-mediated m6A modification stabilized circQKI via IGF2BP2 recognition, leading to its accumulation in resistant cells. In vivo studies confirmed that circQKI overexpression reduced tumor sensitivity to DTX by enhancing autophagy.

Conclusion

circQKI drives DTX resistance via the miR-188-3p/Beclin-1 axis and autophagy activation, with its expression regulated by METTL3-dependent m6A modification and IGF2BP2. Targeting circQKI or autophagy pathways may offer novel therapeutic strategies to overcome DTX resistance in prostate cancer.

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n6 -甲基腺苷修饰的circQKI通过miR-188-3p/Beclin-1途径抑制前列腺癌多西他赛敏感性

多西紫杉醇（DTX）被用于晚期去势抵抗性前列腺癌（CRPC）的一线化疗，但耐药性仍然是一个主要的临床挑战。环状rna （circRNAs）在DTX抗性中发挥关键作用。本研究旨在探讨一种新的circRNA circQKI在DTX抗性中的作用机制及其在CRPC中的调控网络。方法建立sdtx耐药细胞株（PC3/DR和22RV1/DR），通过Sanger测序验证circQKI的环状结构。CircQKI的表达通过siRNA敲低和过表达质粒进行调节。通过CCK-8、流式细胞术和克隆生成试验评估细胞活力、凋亡和集落形成。circQKI和miR-188-3p之间的相互作用通过双荧光素酶报告基因、RIP和RNA下拉验证。Western blot和TEM分析细胞自噬激活情况。皮下异种移植模型评估体内耐药性。通过M6A的RIP-PCR、METTL3/IGF2BP2敲低和稳定性分析来研究M6A的修饰。结果scircqki在耐药细胞中显著上调，通过海绵化miR-188-3p促进DTX耐药，从而增强Beclin-1的表达和自噬激活。抑制Beclin-1或与氯喹（CQ）共处理可部分恢复DTX的敏感性。从机制上讲，mettl3介导的m6A修饰通过IGF2BP2识别稳定了circQKI，导致其在耐药细胞中积累。体内研究证实，circQKI过表达通过增强自噬来降低肿瘤对DTX的敏感性。结论circqki通过miR-188-3p/Beclin-1轴和自噬激活驱动DTX耐药，其表达受mettl3依赖性m6A修饰和IGF2BP2调控。靶向circQKI或自噬途径可能为克服前列腺癌DTX耐药提供新的治疗策略。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.