METTL3 介导的 circGLIS3 m6A 修饰促进了前列腺癌的进展,是 ARSI 治疗的潜在靶点。

IF 9.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Xiaofeng Cheng, Heng Yang, Yujun Chen, Zhenhao Zeng, Yifu Liu, Xiaochen Zhou, Cheng Zhang, An Xie, Gongxian Wang
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引用次数: 0

摘要

背景:环状 RNA(circRNA)已被证明参与了肿瘤的发生和发展。然而,circGLIS3(hsa_circ_0002874)在前列腺癌(PCa)中的作用尚未见报道:方法:通过对公共数据集、PCa 细胞系和组织数据的综合分析,确定了候选 circRNA。进行了一系列细胞功能测试,包括 CCK-8、集落形成、伤口愈合和透孔试验。随后,研究人员利用 RNA 测序、RNA 免疫沉淀、甲基化 RNA 免疫沉淀、microRNA pulldown、荧光素酶报告实验和 Western 印迹等方法探讨了潜在的分子机制。此外,还建立了异种移植肿瘤小鼠模型,以阐明circGLIS3的功能:结果:CircGLIS3源于亲代GLIS3基因的第2外显子,是PCa中一种新型的致癌circRNA,与生化复发密切相关。它在 PCa 组织和细胞系以及恩杂鲁胺高耐药细胞中的表达水平上调。细胞功能测试显示,circGLIS3能促进PCa细胞的增殖、迁移和侵袭。METTL3介导的N6-甲基腺苷(m6A)修饰通过增强其稳定性来维持其上调。从机理上讲,CircGLIS3能使miR-661上调MDM2,从而调节p53信号通路,促进细胞增殖、迁移和侵袭。此外,在体外和体内实验中,circGLIS3的敲除改善了PCa细胞对恩杂鲁胺等ARSI疗法的反应:结论:METTL3介导的circGLIS3 m6A修饰通过miR-661/MDM2轴调控p53信号通路,从而促进了PCa的进展。同时,本研究还揭示了一个治疗PCa的ARSI潜在靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
METTL3-mediated m6A modification of circGLIS3 promotes prostate cancer progression and represents a potential target for ARSI therapy.

Background: Circular RNAs (circRNAs) have been shown to be involved in tumorigenesis and progression. However, the role of circGLIS3 (hsa_circ_0002874) in prostate cancer (PCa) has yet not been reported.

Methods: Candidate circRNA were determined through comprehensive analysis of public datasets, PCa cell lines, and tissues data. A series of cellular functional assays, including CCK-8, colony formation, wound healing, and transwell assays were performed. Subsequently, RNA sequencing, RNA immunoprecipitation, methylated RNA immunoprecipitation, microRNA pulldown, luciferase reporter assay, and western blot were used to explore the underlying molecular mechanisms. Moreover, the xenograft tumor mouse model was established to elucidate the function of circGLIS3.

Results: CircGLIS3, derived from exon 2 of the parental GLIS3 gene, was identified as a novel oncogenic circRNA in PCa that was closely associated with the biochemical recurrence. Its expression levels were upregulated in PCa tissues and cell lines as well as enzalutamide high-resistant cells. The cellular functional assays revealed that circGLIS3 promoted PCa cell proliferation, migration, and invasion. METTL3-mediated N6-methyladenosine (m6A) modification maintained its upregulation by enhancing its stability. Mechanically, CircGLIS3 sponged miR-661 to upregulate MDM2, thus regulating the p53 signaling pathway to promote cell proliferation, migration, and invasion. Furthermore, in vitro and in vivo experiments, the knockdown of circGLIS3 improved the response of PCa cells to ARSI therapies such as enzalutamide.

Conclusions: METTL3-mediated m6A modification of circGLIS3 regulates the p53 signaling pathway via the miR-661/MDM2 axis, thereby facilitating PCa progression. Meanwhile, this study unveils a promising potential target for ARSI therapy for PCa.

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来源期刊
Cellular & Molecular Biology Letters
Cellular & Molecular Biology Letters 生物-生化与分子生物学
CiteScore
11.60
自引率
13.30%
发文量
101
审稿时长
3 months
期刊介绍: Cellular & Molecular Biology Letters is an international journal dedicated to the dissemination of fundamental knowledge in all areas of cellular and molecular biology, cancer cell biology, and certain aspects of biochemistry, biophysics and biotechnology.
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