Targeting CDK12 rescues C/EBPβ-mediated platinum and PARP inhibitor resistance in ovarian cancer

  • Cell Signal. 2025 Dec 16:112328. doi: 10.1016/j.cellsig.2025.112328.
Jiahong Tan  1 ,  Wei Dong  1 ,  Daoqi Wang  2 ,  Aiqing Tu  1 ,  Zuheng Wang  1 ,  Xiaodie Wu  1 ,  Fen Zhang  1 ,  Yun Zhu  1 ,  Li Ren  1 ,  Ying Ai  1 ,  Yun Feng  1 ,  Jie Zhang  3
Affiliations
  • 1. Department of Obstetrics and Gynecology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, PR China.
  • 2. Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, PR China. Electronic address: [email protected].
  • 3. Department of Obstetrics and Gynecology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, PR China. Electronic address: [email protected].
PMID: 41412562 DOI: 10.1016/j.cellsig.2025.112328
Abstract

Despite multimodality treatment efforts, resistance to platinum and PARP inhibitors represents a primary impediment to improve prognosis of ovarian Cancer. Here, we found that ovarian Cancer tissues had higher C/EBPβ expression compared with normal tissues and high C/EBPβ expression predicted unfavorable survival outcomes. Elevated C/EBPβ expression enhanced cisplatin resistance and olaparib resistance. C/EBPβ could affect DDR signals of ovarian Cancer. CDK12, serving as a C/EBPβ-regulated DDR-related gene, was directly targeted by and bound with C/EBPβ. C/EBPβ could promote CDK12 expression and confer drug tolerance via CDK12. Manipulation of CDK12 could reverse the effects of C/EBPβ. Using CDK12 Inhibitor THZ531 could rescue C/EBPβ-mediated cisplatin resistance and olaparib resistance. Our findings indicated that C/EBPβ is a potent DDR regulator of ovarian Cancer, which directly targets CDK12 and upregulates its expression. High C/EBPβ expression mediates platinum resistance and PARP Inhibitor resistance via CDK12. Targeting C/EBPβ via CDK12 inhibition could rescue drug responsiveness of ovarian Cancer, thereby counteracting platinum and PARP Inhibitor resistance. C/EBPβ could thus be exploited as a candidate prognostic biomarker in ovarian Cancer.

Keywords
Olaparib resistance; Ovarian cancer; Platinum resistance; Prognostic biomarker; Therapeutic target.
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