CYP1B1 通过组蛋白 H1.4 相互作用和染色质可及性的增加促进卵巢癌的 PARPi- 抗性

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates Pub Date : 2024-09-12 DOI:10.1016/j.drup.2024.101151

Yite Xue , Taotao Yin , Shuo Yuan , Lingfang Wang , Hui Lin , Tianzhe Jin , Ruiyi Xu , Jiaxin Gu , Shizhen Shen , Xiaojing Chen , Zhuoye Chen , Ni Sima , Lifeng Chen , Weiguo Lu , Xiao Li , Xiaodong Cheng , Hui Wang

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引用次数: 0

摘要

导言卵巢癌是致死率最高的妇科癌症，给治疗带来了巨大挑战。PARP抑制剂（PARPi）与同源重组缺陷之间合成致死性的发现标志着治疗BRCA1/2基因突变肿瘤的新时代的到来。然而，PARPi的耐药性仍然是临床面临的一大挑战。方法用RNA测序鉴定PARPi治疗改变的基因，用LC-MS检测与CYP1B1相互作用的蛋白质。通过 ATAC-seq 和基因表达操作探索了耐药机制。其他技术包括微球核酸酶消化试验、DAPI染色和荧光显微镜，用于评估核形态和染色质可及性的变化。结果奥拉帕利的逐渐暴露培养出了PARPi耐药细胞系A2780-OlaR，它在RNA和蛋白质水平上都表现出CYP1B1的显著上调。下调 CYP1B1 表达或使用特异性抑制剂会降低细胞对奥拉帕利的反应。链接组蛋白 H1.4 被确定与 CYP1B1 相关。ATAC-seq显示A2780-OlaR和亲代细胞的染色质可及性存在差异，表明H1.4的下调与染色质可及性的增加以及奥拉帕利处理后细胞存活率的提高有关。这项研究强调了染色质可及性在 PARPi 疗效中的重要性，并建议将 CYP1B1/H1.4 轴作为克服卵巢癌耐药性的治疗靶点，从而提供潜在的治疗益处。

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

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.

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来源期刊

Drug Resistance Updates 医学-药学

CiteScore

26.20

自引率

11.90%

发文量

审稿时长

29 days

期刊介绍： Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research