Modulation of HAT activity by the BRCA2 genotype : a potential mechanism of taxanes resistance

Abstract

Taxanes are a class of anticancer agents, which stabilize polymerized microtubules and enhance microtubule assembly, and thus arrest the cell cycle in G2/M phases, leading to cell death. Taxanes resistance has been attributed to a variety of mechanisms. But the evidence for this resistant mechanism is weak. In the present study, we defined the resistance mechanism to taxanes based on BRCA2 genotype. First, we screened taxanes-sensitivity by MTT assay. We identified a significant difference in chemosensitivity related to BRCA2 372Asn>His genotype. This difference was reflected in a higher IC50 for heterozygous polymorphic type than for the wild type. The BRCA2 and P/CAF expression were no difference among groups. However, we showed that the interaction of BRCA2 and P/CAF decreased by 2-fold in the heterozygous polymorphic type compared with the wild type. HAT activity was also relatively higher in BRCA2 wild type cells compared with heterozygous polymorphic cells. Functional validation of selected SNP by HDAC inhibition was used to indirectly confirm that our selection was reasonable. To directly confirm, we established cell lines with an altered BRCA2 genotype. The cell lines with an altered BRCA2 genotype were restored to taxanes-sensitivity. The functional restoration by transfection of altered genotypes suggests that HAT activity and BRCA2-P/CAF interaction related to the BRCA2 genotype may be a potential mechanism of taxanes resistance in breast cancer. In conclusion, HAT activity based on BRCA2-P/CAF interaction had potental role of taxanes-sensitivity in breast cancer cells.