CYP1B1 promotes PARPi-resistance via histone H1.4 interaction and increased chromatin accessibility in ovarian cancer

  • Drug Resist Updat. 2024 Sep 12:77:101151. doi: 10.1016/j.drup.2024.101151.
Yite Xue  1 ,  Taotao Yin  1 ,  Shuo Yuan  1 ,  Lingfang Wang  1 ,  Hui Lin  1 ,  Tianzhe Jin  1 ,  Ruiyi Xu  1 ,  Jiaxin Gu  1 ,  Shizhen Shen  1 ,  Xiaojing Chen  1 ,  Zhuoye Chen  1 ,  Ni Sima  1 ,  Lifeng Chen  2 ,  Weiguo Lu  3 ,  Xiao Li  4 ,  Xiaodong Cheng  5 ,  Hui Wang  6
Affiliations
  • 1. Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China; Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Reproductive Health Research, Hangzhou, China.
  • 2. Department of Gynecology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 3. Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China; Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Reproductive Health Research, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China.
  • 4. Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China; Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Reproductive Health Research, Hangzhou, China. Electronic address: [email protected].
  • 5. Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China; Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Reproductive Health Research, Hangzhou, China. Electronic address: [email protected].
  • 6. Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China; Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Reproductive Health Research, Hangzhou, China. Electronic address: [email protected].
PMID: 39395328 DOI: 10.1016/j.drup.2024.101151
Abstract

Introduction: Ovarian Cancer is the most lethal gynecological Cancer and presents significant therapeutic challenges. The discovery of synthetic lethality between PARP inhibitors (PARPi) and homologous recombination deficiency marked a new era in treating BRCA1/2-mutated tumors. However, PARPi resistance remains a major clinical challenge.

Methods: RNA Sequencing was used to identify genes altered by PARPi treatment and LC-MS was used to detect proteins interacting with CYP1B1. Resistance mechanisms were explored through ATAC-seq and gene expression manipulation. Additional techniques, including micrococcal nuclease digestion assays, DAPI staining, and fluorescence microscopy, were used to assess changes in nuclear morphology and chromatin accessibility.

Results: The gradual exposure of Olaparib has developed a PARPi-resistant cell line, A2780-OlaR, which exhibits significant upregulation of CYP1B1 at both RNA and protein levels. Down-regulating CYP1B1 expression or using specific inhibitors decreased the cellular response to Olaparib. Linker histone H1.4 was identified as associated with CYP1B1. ATAC-seq showed differential chromatin accessibility between A2780-OlaR and parental cells, indicating that the downregulation of H1.4 was associated with increased chromatin accessibility and higher cell viability after Olaparib treatment.

Conclusion: Our findings reveal a novel role for CYP1B1 in driving PARPi resistance through distinct molecular mechanisms in A2780-OlaR. This study highlights the importance of chromatin accessibility in PARPi efficacy and suggests the CYP1B1/H1.4 axis as a promising therapeutic target for overcoming drug resistance in ovarian Cancer, offering potentially therapeutic benefits.

Keywords
Chromatin accessibility; Ovarian cancer; PAPRi resistance; Targeted therapy; Treatment targets.
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