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

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

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: 5198008@zju.edu.cn.
  • 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: chengxd@zju.edu.cn.
  • 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: wang71hui@zju.edu.cn.
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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