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5-methylcytosine regulated CCNL2 promotes cisplatin resistance by ferroptosis inhibition in ovarian cancer

ABSTRACT: Ovarian cancer (OC) is the most lethal gynecological tumor, primarily due to resistance to chemotherapy. Cyclin L2 (CCNL2), a novel member of the cyclin family, plays an important role in HIV replication. However, its role in OC chemoresistance remains unknown. Here, we demonstrate that elevated expression of CCNL2 indicates a poor prognosis in ovarian cancer. Furthermore, inhibition of CCNL2 reduces malignancy and enhances chemotherapy sensitivity in OC. Additionally, CCNL2 inhibition promotes cisplatin-induced ferroptosis by increasing intracellular iron ion levels. Mechanistically, CCNL2 is upregulated by YBX1 via a 5-methylcytosine (m5C) manner, leading to increased CCNL2 mRNA stability. Given the lack of protein structure data for CCNL2, we performed virtual screening to identify YBX1 inhibitors, targeting its upstream regulation. The inhibitor YB-B1 effectively suppresses YBX1 and CCNL2 expression, and enhances the cytotoxic effect of cisplatin. Together, we highlight the critical role of CCNL2 in ovarian cancer chemoresistance, elucidate its regulatory mechanism, and propose a new approach to address the challenge.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279620 | GEO | 2025/06/25

REPOSITORIES: GEO

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Project description:Multiple DNA methylation changes have been associated with the acquisition of drug resistance; however it remains uncertain how many of these changes may represent critical DNA methylation drivers of chemoresistance. Using genome-wide DNA methylation profiling across 27,578 CpG sites on Illumina HumanMethylation27 bead array we identified loci at 4092 genes becoming hypermethylated in the chemoresistant A2780/cp70 ovarian tumour cell line compared to the parental sensitive A2780 line. Hypermethylation at CpG islands (CGI) is often associated with transcriptional silencing, however only 245 of these hypermethylated genes become down-regulated in A2780/cp70 as measured by microarray expression profiling. Treatment with the demethylating agent Decitabine induces re-sensitisation to cisplatin and resulted in re-expression of 41 of the down-regulated genes in cisplatin-resistant cells at the time point when re-sensitisation occurs. 13 of the 41 genes were consistently hypermethylated in two further independent cisplatin-resistant A2780 cell derivatives. Nine out of the 13 genes (ARHGDIB, ARMCX2, COL1A, FLNA, FLNC, MEST, MLH1, NTS, PSMB9) acquired methylation at CpG sites in ovarian tumours at relapse following chemotherapy or chemoresistant cell lines derived at the time of patient relapse. Furthermore, 5/13 candidate genes acquired methylation in drug-resistant in vivo-derived ovarian cancer sustaining (side population) cells. Therefore, this small set of genes are potential key drivers of chemoresistance and should be further evaluated as predictive biomarkers, both to existing chemotherapies, but also to epigenetic therapies used to modulate drug resistance. Array-based methylation profiling was performed using the Infinium HumanMethylation27 BeadChip in two cisplatin sensitive cell lines and three cisplatin resistant cell lines derived in vitro, four pairs of cisplatin sensitive and resistant cell lines derived in vivo, 7 pairs of tumour tissues obtained from patients before chemotherapy and at disease relapse, 2 pairs of IGROV1 SP and NSP cells. The reproducibility of the Infinium HumanMethylation27 BeadChips was evaluated using biological and technical replicates of matched chemosensitive/chemoresistant ovarian cancer cell lines PEO1/PEO4. Differential methylation cutoff was estimated from two biological replicates by bootstrap resampling.

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5-methylcytosine regulated CCNL2 promotes cisplatin resistance by ferroptosis inhibition in ovarian cancer

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