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Modulation of HAT activity by the BRCA2 N372H variation is a novel mechanism of paclitaxel resistance in breast cancer cell lines

 Woo Sun Kwon  ;  Sun Young Rha  ;  Hei-Cheul Jeung  ;  Tae Soo Kim  ;  Hyun Cheol Chung 
 Biochemical Pharmacology, Vol.138 : 163-173, 2017 
Journal Title
 Biochemical Pharmacology 
Issue Date
Acetylation/drug effects ; Amino Acid Substitution ; Antineoplastic Agents, Phytogenic/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology* ; BRCA2 Protein/genetics* ; BRCA2 Protein/metabolism ; Breast Neoplasms/drug therapy* ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Resistance, Neoplasm/drug effects* ; Female ; Heterozygote ; Histone Deacetylase Inhibitors/pharmacology* ; Histone Deacetylases/chemistry ; Histone Deacetylases/metabolism* ; Humans ; Mutation ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Paclitaxel/pharmacology* ; Polymorphism, Single Nucleotide ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/metabolism ; Tubulin Modulators/pharmacology ; p300-CBP Transcription Factors/genetics ; p300-CBP Transcription Factors/metabolism
BRCA2 N372H ; HAT activity ; P/CAF ; Taxane resistance
Paclitaxel stabilizes microtubule polymerization, enhances microtubule assembly, and G2/M arrests, leading to cell death. Paclitaxel resistance has been attributed to a variety of mechanisms. In the present study, we define a new resistance mechanism to paclitaxel based on BRCA2 variation. Chemo-sensitivity to paclitaxel based on the variations was compared. Restoration of paclitaxel sensitivity was induced indirectly with combined treatment of paclitaxel and HDAC inhibitor. Variant and wild type of BRCA2 clones were obtained from wild and variant cells, respectively. Chemo-sensitivity, P/CAF and BubR1 expression and acetylation, BRCA2-P/CAF and BRCA2-BubR1 interactions, and HAT activities of the clones with BRCA2 variation were compared. We identified an association between chemo-sensitivity and BRCA2 N372H variation. The IC50 of paclitaxel in heterozygous variation was higher than that of wild type. There were no differences in basic expression levels of BRCA2 among variant types. However, P/CAF expression, of BRCA2-P/CAF interaction, and HAT activity were significantly lower in heterozygous variants than in the wild type. After HDAC inhibitor treatment, HAT activity and paclitaxel sensitivity were restored in variant cells. Cell lines transformed from wild to variant or from variant to wild showed reciprocal changes in P/CAF expression, BRCA2-P/CAF interaction, HAT activity, and paclitaxel sensitivity. Forced expression of the BRCA2 heterozygous variant induced paclitaxel resistance due to altered HAT activity (p<0.001). This was reversed by the TSA combination. Restoration of wild BRCA2 from variant type improved paclitaxel sensitivity (p<0.001). Modulation of HAT activity by BRCA2 N372H variation is a new mechanism of paclitaxel resistance in breast cancer.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
김태수(Kim, Tae Soo)
라선영(Rha, Sun Young) ORCID logo https://orcid.org/0000-0002-2512-4531
정현철(Chung, Hyun Cheol) ORCID logo https://orcid.org/0000-0002-0920-9471
정희철(Jeung, Hei Cheul) ORCID logo https://orcid.org/0000-0003-0952-3679
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