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<p>Ovarian cancer (OV) is a leading cause of mortality related to gynecological malignancies. Chemoresistance represents a major clinical obstacle. Carboplatin (CBP) is a first-line chemotherapeutic agent widely used for ovarian cancer treatment. Meanwhile, Zinc Finger CCCH-Type Containing 18 (ZC3H18) is aberrantly overexpressed in OV. However, its functional role and underlying regulatory mechanisms in CBP resistance remain undefined. Ovarian cancer cell lines A2780 and ES‑2 and their CBP‑resistant sublines (A2780/CBP and ES‑2/CBP) were used in this study. The resistant cell lines were established by exposing parental cells to gradually increasing concentrations of CBP for two months. Western blotting, IHC, and RT-qPCR were used to detect gene and protein expression. CCK-8, EdU, and flow cytometry analyses were used to measure cell viability, proliferation, and apoptosis. A Seahorse XFp extracellular flux analyzer and a commercial kit were used to evaluate mitochondrial function. Co-IP was used to validate protein interactions. MSP was performed to analyze BRCA1 methylation. ZC3H18 expression was significantly elevated in CBP-resistant OV tissues and cell lines and was associated with poor patient prognosis. ZC3H18 silencing in resistant cells reduced mitochondrial OCR and ATP production, suppressed proliferation, and enhanced CBP-induced apoptosis. Mechanistically, USP39 directly interacted with and deubiquitinated ZC3H18, thereby enhancing its protein stability. ZC3H18, in turn, promoted BRCA1 expression by reducing methylation of the BRCA1 promoter. Furthermore, USP39 knockdown sensitized resistant cells to CBP, an effect that was partially reversed by ZC3H18 overexpression, which restored BRCA1 expression, mitochondrial function, and chemoresistance. USP39-mediated deubiquitination stabilized ZC3H18, which suppressed BRCA1 promoter methylation and enhanced mitochondrial biogenesis, thereby promoting CBP resistance in ovarian cancer. Targeting the USP39/ZC3H18/BRCA1 axis may offer a novel strategy for overcoming chemoresistance.</p>

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USP39 reduces BRCA1 methylation to promote mitochondrial biogenesis and lower drug sensitivity in ovarian cancer through deubiquitinating ZC3H18

  • 期刊论文

  • 发表日期：

    2026年5月25日

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  • Jing Wang,
  • Xinyu Li,
  • Jianmiao Chang,
  • Xiaoxue Hou,
  • Yanan Yan,
  • Jiangping Chen,
  • Xin Wu

摘要

Ovarian cancer (OV) is a leading cause of mortality related to gynecological malignancies. Chemoresistance represents a major clinical obstacle. Carboplatin (CBP) is a first-line chemotherapeutic agent widely used for ovarian cancer treatment. Meanwhile, Zinc Finger CCCH-Type Containing 18 (ZC3H18) is aberrantly overexpressed in OV. However, its functional role and underlying regulatory mechanisms in CBP resistance remain undefined. Ovarian cancer cell lines A2780 and ES‑2 and their CBP‑resistant sublines (A2780/CBP and ES‑2/CBP) were used in this study. The resistant cell lines were established by exposing parental cells to gradually increasing concentrations of CBP for two months. Western blotting, IHC, and RT-qPCR were used to detect gene and protein expression. CCK-8, EdU, and flow cytometry analyses were used to measure cell viability, proliferation, and apoptosis. A Seahorse XFp extracellular flux analyzer and a commercial kit were used to evaluate mitochondrial function. Co-IP was used to validate protein interactions. MSP was performed to analyze BRCA1 methylation. ZC3H18 expression was significantly elevated in CBP-resistant OV tissues and cell lines and was associated with poor patient prognosis. ZC3H18 silencing in resistant cells reduced mitochondrial OCR and ATP production, suppressed proliferation, and enhanced CBP-induced apoptosis. Mechanistically, USP39 directly interacted with and deubiquitinated ZC3H18, thereby enhancing its protein stability. ZC3H18, in turn, promoted BRCA1 expression by reducing methylation of the BRCA1 promoter. Furthermore, USP39 knockdown sensitized resistant cells to CBP, an effect that was partially reversed by ZC3H18 overexpression, which restored BRCA1 expression, mitochondrial function, and chemoresistance. USP39-mediated deubiquitination stabilized ZC3H18, which suppressed BRCA1 promoter methylation and enhanced mitochondrial biogenesis, thereby promoting CBP resistance in ovarian cancer. Targeting the USP39/ZC3H18/BRCA1 axis may offer a novel strategy for overcoming chemoresistance.