1. CYP1B1 promotes PARPi-resistance via histone H1.4 interaction and increased chromatin accessibility in ovarian cancer.
- Author
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Xue Y, Yin T, Yuan S, Wang L, Lin H, Jin T, Xu R, Gu J, Shen S, Chen X, Chen Z, Sima N, Chen L, Lu W, Li X, Cheng X, and Wang H
- Subjects
- Humans, Female, Cell Line, Tumor, Piperazines pharmacology, Gene Expression Regulation, Neoplastic drug effects, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Ovarian Neoplasms metabolism, Cytochrome P-450 CYP1B1 genetics, Cytochrome P-450 CYP1B1 metabolism, Drug Resistance, Neoplasm drug effects, Chromatin metabolism, Chromatin drug effects, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Histones metabolism, Phthalazines pharmacology
- 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., Competing Interests: Declaration of Competing Interest All authors declared that there was no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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