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

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