Chromatin-focused genetic and chemical screens identify BRPF1 as a targetable vulnerability in Taxol-resistant triple-negative breast cancer

• Published in: Experimental & molecular medicine Vol. 57; no. 6; pp. 1294 - 1307
• Main Authors: Yedier-Bayram, Ozlem, Cingöz, Ahmet, Yilmaz, Ebru, Aksu, Ali Cenk, Esin, Beril, Degirmenci, Nareg, Cavga, Ayse Derya, Dedeoğlu, Beyza, Cevatemre, Buse, Syed, Hamzah, Philpott, Martin, Cribbs, Adam P., Oppermann, Udo, Lack, Nathan A., Acilan, Ceyda, Onder, Tamer T., Bagci-Onder, Tugba
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2025; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13/1; 13/109; 13/31; 13/89; 14/63; 38/22; 38/91; 42; 42/47; 631/337/176; 631/67/1059/99; 631/67/1347; 692/699/67/1059/2326; 96/98; ABC transporters; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Artificial intelligence; ATP Binding Cassette Transporter, Subfamily B - genetics; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer; Cancer therapies; Cell Line, Tumor; Cell viability; Chemoresistance; Chemotherapy; Chromatin; Chromatin - genetics; Chromatin - metabolism; DNA methylation; DNA structure; Drug dosages; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Epigenesis, Genetic; Epigenetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Histone acetyltransferase; Humans; Medical Biochemistry; Molecular Medicine; Multidrug resistance; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Paclitaxel; Paclitaxel - pharmacology; Phenotypes; Proteins; Stem Cells; Toxicity; Transcriptomes; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumors; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-025-01466-5

Triple-negative breast cancer (TNBC) is a particularly aggressive and frequently recurring form of breast cancer, where chemotherapy is the primary treatment approach. Unfortunately, the development of resistance to chemotherapy poses a considerable challenge, restricting the already limited therapeutic alternatives for recurrent cases. Here, we generated two Taxol-resistant TNBC cell lines with a dose-escalation method to mimic chemotherapy resistance in vitro. These cells exhibited reduced growth rates, altered morphology and evasion of apoptosis. Transcriptome analysis uncovered elevated ABCB1 expression and multidrug-resistant phenotype in these resistant cells. To comprehensively investigate the key epigenetic regulators of Taxol resistance, we conducted chromatin-focused genetic and chemical screens and pinpointed Bromodomain and PHD Finger Containing 1 (BRPF1) as a novel regulator of Taxol resistance. Knockout of BRPF1, the reader protein in the MOZ–MORF histone acetyltransferase complex, but not the other complex members, sensitized resistant cells to Taxol. In addition, BRPF1 inhibitors, PFI-4 and OF-1, in combination with Taxol significantly reduced cell viability. Transcriptome analysis upon BRPF1 loss or inhibition revealed a negative impact on ribosome biogenesis-related gene sets, resulting in a global decrease in protein translation in Taxol-resistant cells. CUT&RUN-qPCR analysis demonstrated that BRPF1 directly binds to the ABCB1 promoter, enhancing its expression toward inducing a multidrug-resistant phenotype. Conversely, knockout or inhibition of BRPF1 leads to decreased ABCB1 expression. Our findings uncover a comprehensive molecular framework, highlighting the pivotal role of epigenetic reader protein BRPF1 in Taxol resistance and providing potential avenues for therapeutic intervention in TNBC. Targeting BRPF1 offers hope against Taxol resistance Triple-negative breast cancer (TNBC) is a challenging type of breast cancer that lacks targeted treatment options. Researchers aimed to understand why some TNBC cells become resistant to the chemotherapy drug Taxol and focused on the role of a protein called BRPF1 in this resistance. They created Taxol-resistant TNBC cells in the laboratory and found that these cells had high levels of a protein called ABCB1, which helps to pump drugs out of cells. They used advanced techniques to identify key proteins involved in this resistance and discovered that BRPF1, part of a complex that modifies DNA structure, plays a crucial role. By using genetic tools and chemical inhibitors to reduce BRPF1 activity, they found that the resistant cells became more sensitive to Taxol. This suggests that targeting BRPF1 could be a new way to treat resistant TNBC. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.