Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis.

IF 6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Medicine Pub Date : 2024-06-17 DOI:10.1186/s10020-024-00857-0

Hongwei Zhang, Zixuan Wang, Xiaolong Qiao, Nan Peng, Jiaxing Wu, Yinan Chen, Chuandong Cheng

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Abstract

Glioma is the most common malignant tumor of the central nervous system, with EZH2 playing a crucial regulatory role. This study further explores the abnormal expression of EZH2 and its mechanisms in regulating glioma progression. Additionally, it was found that IHMT-337 can potentially be a therapeutic agent for glioma. The prognosis, expression, and localization of EZH2 were determined using bioinformatics, IHC staining, Western blot (WB) analysis, and immunofluorescence (IF) localization. The effects of EZH2 on cell function were assessed using CCK-8 assays, Transwell assays, and wound healing assays. Public databases and RT-qPCR were utilized to identify downstream targets. The mechanisms regulating these downstream targets were elucidated using MS-PCR and WB analysis. The efficacy of IHMT-337 was demonstrated through IC50 measurements, WB analysis, and RT-qPCR. The effects of IHMT-337 on glioma cells in vitro were evaluated using Transwell assays, EdU incorporation assays, and flow cytometry. The potential of IHMT-337 as a treatment for glioma was assessed using a blood-brain barrier (BBB) model and an orthotopic glioma model. Our research confirms significantly elevated EZH2 expression in gliomas, correlating with patient prognosis. EZH2 facilitates glioma proliferation, migration, and invasion alongside promoting SLC12A5 DNA methylation. By regulating SLC12A5 expression, EZH2 activates the WNK1-OSR1-NKCC1 pathway, enhancing its interaction with ERM to promote glioma migration. IHMT-337 targets EZH2 in vitro to inhibit WNK1 activation, thereby suppressing glioma cell migration. Additionally, it inhibits cell proliferation and arrests the cell cycle. IHMT-337 has the potential to cross the BBB and has successfully inhibited glioma progression in vivo. This study expands our understanding of the EZH2-SLC12A5 axis in gliomas, laying a new foundation for the clinical translation of IHMT-337 and offering new insights for precision glioma therapy.

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揭示 IHMT-337 在胶质瘤治疗中的治疗潜力：靶向 EZH2-SLC12A5 轴。

胶质瘤是中枢神经系统最常见的恶性肿瘤，EZH2在其中发挥着重要的调控作用。本研究进一步探讨了 EZH2 的异常表达及其调控胶质瘤进展的机制。此外，研究还发现 IHMT-337 有可能成为胶质瘤的治疗药物。研究采用生物信息学、IHC染色、Western印迹（WB）分析和免疫荧光（IF）定位等方法确定了EZH2的预后、表达和定位。使用 CCK-8 试验、Transwell 试验和伤口愈合试验评估了 EZH2 对细胞功能的影响。利用公共数据库和 RT-qPCR 确定了下游靶标。利用 MS-PCR 和 WB 分析阐明了这些下游靶点的调控机制。通过 IC50 测量、WB 分析和 RT-qPCR 证明了 IHMT-337 的疗效。使用Transwell试验、EdU掺入试验和流式细胞术评估了IHMT-337对体外胶质瘤细胞的影响。使用血脑屏障（BBB）模型和正位胶质瘤模型评估了 IHMT-337 治疗胶质瘤的潜力。我们的研究证实，胶质瘤中 EZH2 的表达明显升高，这与患者的预后有关。EZH2 在促进 SLC12A5 DNA 甲基化的同时，还能促进胶质瘤的增殖、迁移和侵袭。通过调节 SLC12A5 的表达，EZH2 激活了 WNK1-OSR1-NKCC1 通路，增强了其与 ERM 的相互作用，从而促进胶质瘤的迁移。IHMT-337 在体外靶向 EZH2，抑制 WNK1 的活化，从而抑制胶质瘤细胞的迁移。此外，它还能抑制细胞增殖并阻滞细胞周期。IHMT-337 有可能穿过 BBB，并成功抑制了胶质瘤在体内的发展。这项研究拓展了我们对胶质瘤中EZH2-SLC12A5轴的认识，为IHMT-337的临床转化奠定了新的基础，并为胶质瘤的精准治疗提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.