Targeted inhibition of JMJD2C/MALAT1 axis compensates for the deficiency of metformin in reversing ovarian cancer platinum resistance

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-04-24 DOI:10.1016/j.lfs.2025.123663

Linlin Li , Jialin Zhang , Huiqing Li , Liying Qin , Han Wu , Zijiao Li , Lei Cai , Di Chen , Jianping Yang , Yibing Chen , Ya Xie

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引用次数: 0

Abstract

Aims

We explored JMJD2C’s role in platinum resistance in ovarian cancer and its modulation by metformin to propose strategies for overcoming treatment limitations.

Materials and methods

JMJD2C and MALAT1 expression was assessed via RT-qPCR, western blotting, and immunohistochemical assays using OC cell lines, tissue from OC patients, and xenograft treatment with or without metformin. CCK-8 assays, flow cytometry, inductively coupled plasma mass spectrometry, luciferase reporter assays, and ChIP assays were employed to evaluate the impact of JMJD2C/MALAT1 on PR and the effects of metformin on JMJD2C. The effects of metformin in combination with JMJD2C knockdown were assessed in vitro and in vivo.

Key findings

JMJD2C and MALAT1 expression was higher in tissue samples from platinum-resistant phase compared to those from paired platinum-sensitive phase. JMJD2C upregulated MALAT1 in platinum-resistant ovarian cancer (PROC) cells by demethylating its promoter at sites H3K9m3 and H3K36m3. Overexpression of JMJD2C or MALAT1 promoted PR by activating NF-κB/P-gp and P38 MAPK/ERCC1 signaling pathways, with their knockdown produced the opposite effect. Metformin increased JMJD2C expression in tumor tissue, cell lines, and a xenograft model of OC; however, elevated JMJD2C expression attenuated the PR-reversal efficacy of low-concentration metformin. Low-dose metformin combined with JMJD2C-knockdown effectively reversed PR both in in vitro and in vivo, achieving better results than either treatment alone.

Significance

JMJD2C drives PR in OC by demethylating the MALAT1 promoter. Metformin upregulated JMJD2C expression, thus necessitating a higher effective dosage of metformin. Targeted inhibition of JMJD2C synergistically enhanced the efficacy of low-dose metformin in overcoming PR, thus providing a promising approach for addressing PR.

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靶向抑制JMJD2C/MALAT1轴补偿二甲双胍缺乏逆转卵巢癌铂耐药

目的：探讨JMJD2C在卵巢癌铂耐药中的作用以及二甲双胍对其的调节作用，以提出克服治疗局限性的策略。材料和方法通过RT-qPCR、western blotting和免疫组化分析评估sjmjd2c和MALAT1的表达，使用OC细胞系、OC患者组织和使用或不使用二甲双胍的异种移植治疗。采用CCK-8法、流式细胞术、电感耦合血浆质谱法、荧光素酶报告基因法和ChIP法评估JMJD2C/MALAT1对PR的影响以及二甲双胍对JMJD2C的影响。在体外和体内评估二甲双胍联合JMJD2C敲除的效果。关键发现：与配对铂敏感期的组织样本相比，铂耐药期的组织样本中sjmjd2c和MALAT1的表达更高。JMJD2C通过在H3K9m3和H3K36m3位点上去甲基化其启动子，上调铂耐药卵巢癌（PROC）细胞中的MALAT1。JMJD2C或MALAT1过表达通过激活NF-κB/P-gp和P38 MAPK/ERCC1信号通路促进PR，而它们的敲低则产生相反的效果。二甲双胍增加肿瘤组织、细胞系和OC异种移植模型中JMJD2C的表达；然而，升高的JMJD2C表达减弱了低浓度二甲双胍逆转pr的效果。低剂量二甲双胍联合jmjd2c敲低在体外和体内均能有效逆转PR，效果优于单独治疗。ejmjd2c通过去甲基化MALAT1启动子来驱动OC中的PR。二甲双胍上调了JMJD2C的表达，因此需要更高的二甲双胍有效剂量。靶向抑制JMJD2C可协同增强低剂量二甲双胍治疗PR的疗效，为解决PR提供了一种有前景的方法。

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

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.