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Series GSE262577 Query DataSets for GSE262577
Status Public on May 14, 2024
Title Chromatin-focused genetic and chemical screens identify BRPF1 as a targetable vulnerability in Taxol-resistant triple-negative breast cancer [CRISPR]
Organism Homo sapiens
Experiment type Other
Summary Triple-negative breast cancer (TNBC) stands out as a particularly aggressive and frequently recurring form of breast cancer. Due to the absence of hormone receptors, the available treatment avenues are constrained, making chemotherapy the primary approach. Unfortunately, the development of resistance to chemotherapy poses a significant challenge, further restricting the already limited therapeutic alternatives for recurrent cases. Understanding the molecular basis of chemotherapy resistance in TNBC is pivotal for improving treatment outcomes. Here, we generated two different Taxol-resistant TNBC cell lines with dose-escalation method to mimic chemotherapy resistance in vitro. These cells exhibited hallmark features of resistance, including reduced cell growth, altered morphology, and resistance to apoptosis. Transcriptome analysis uncovered elevated ABCB1 expression and multidrug-resistant phenotype in the resistant cells. To comprehensively investigate the key epigenetic regulators of Taxol resistance, we conducted epigenome-wide CRISPR/Cas9 and chemical probe library screens. Both screens pinpointed Bromodomain and PHD Finger Containing 1 (BRPF1) which is the reader protein in MOZ/MORF histone acetyl-transferase complex, as the regulator of Taxol resistance in TNBC cells. Knockout of BRPF1, but not the other members of the MOZ/MORF complex, sensitized resistant cells to Taxol. Additionally, 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. Our ChIP-qPCR analysis further demonstrated that active BRPF1 directly interacts with the ABCB1 promoter, enhancing its expression and inducing a multidrug-resistant phenotype. Conversely, knockout or inhibition of BRPF1 leads to decreased ABCB1 expression. This dual mechanism critically sensitizes Taxol-resistant TNBC cells to chemotherapy. 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.
 
Overall design To mimic chemotherapy resistance in vitro, we generated Taxol-resistant SUM159PT cell lines, namely T1-160 and T2-450. We first performed RNA-seq to uncover the differentially expressed genes in resistant cells when compared to parental cells. Later, we identified BRPF1 as a regulator of taxol resistance in T1-160 cells through epigenome-wide CRISPR/Cas9 screening and performed validation experiments using inhibitors or knockouts.
Web link https://www.biorxiv.org/content/10.1101/2024.04.16.587277v1
 
Contributor(s) Bayram OY, Cingöz A, Yilmaz E, Aksu AC, Esin B, Pinarbasi-Degirmenci N, Cavga AD, Dedeoglu B, Cevatemre B, Syed H, Philpott M, Cribbs AP, Oppermann U, Lack NA, Ayhan CA, Önder TT, Bagci-Onder T
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Submission date Mar 27, 2024
Last update date May 14, 2024
Contact name Tugba Bagci-Onder
E-mail(s) tuonder@ku.edu.tr
Organization name Koç University
Department Koç University Research Center for Translational Medicine
Street address Rumelifeneri Yolu, Sarıyer
City İstanbul
ZIP/Postal code 34450
Country Turkey
 
Platforms (1)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
Samples (8)
GSM8171927 T1-AP-1
GSM8171928 T1-AP-3
GSM8171929 T1-DMSO-1
Relations
BioProject PRJNA1092582

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE262577_SUM159-T1-160_DMSO123vsAP123_nt.sgrna_summary.txt.gz 441.5 Kb (ftp)(http) TXT
GSE262577_SUM159-T1-160_TAX123vsAP123_nt.sgrna_summary.txt.gz 437.3 Kb (ftp)(http) TXT
GSE262577_SUM159-T1-160_TAX123vsDMSO123_nt.sgrna_summary.txt.gz 430.2 Kb (ftp)(http) TXT
GSE262577_T1-DMSOvsAP_gene_summary.txt.gz 15.0 Kb (ftp)(http) TXT
GSE262577_T1-TaxvsAP_gene_summary.txt.gz 15.0 Kb (ftp)(http) TXT
GSE262577_T1-TaxvsDMSO_gene_summary.txt.gz 33.0 Kb (ftp)(http) TXT
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