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
  • 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: [email protected].
  • 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: [email protected].
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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