2. Academic Validation
  3. Targeted inhibition of JMJD2C/MALAT1 axis compensates for the deficiency of metformin in reversing ovarian cancer platinum resistance

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

  • Life Sci. 2025 Jul 15:373:123663. doi: 10.1016/j.lfs.2025.123663.
Linlin Li 1,  Jialin Zhang 2,  Huiqing Li 2,  Liying Qin 3,  Han Wu 2,  Zijiao Li 2,  Lei Cai 2,  Di Chen 4,  Jianping Yang 5,  Yibing Chen 6,  Ya Xie 7
Affiliations

Affiliations

  • 1 Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, Henan, PR China; Academy of Medical Sciences, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, Henan, PR China.
  • 2 Department of Gynecology and Obstetrics, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, Henan, PR China.
  • 3 Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, Henan, PR China.
  • 4 Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases of Henan Province, and School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, PR China.
  • 5 Department of Pathology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, Henan, PR China.
  • 6 Department of Gynecology and Obstetrics, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, Henan, PR China. Electronic address: chenyibing@zzu.edu.cn.
  • 7 Department of Gynecology and Obstetrics, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, Henan, PR China. Electronic address: fccxiey@zzu.edu.cn.
PMID: 40280301 DOI: 10.1016/j.lfs.2025.123663
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.

Keywords

ERCC1; JMJD2C; MALAT1; Metformin; Ovarian cancer; P-gp; Platinum resistance.

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