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

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2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)163-173
Number of pages11
JournalBiochemical Pharmacology
Volume138
DOIs
Publication statusPublished - 2017 Aug 15

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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