Inhibition of N-acetyltransferase 10 using remodelin attenuates doxorubicin resistance by reversing the epithelial-mesenchymal transition in breast cancer.

Development of resistance to doxorubicin-based chemotherapy limits curative effect in breast cancer (BC). N-acetyltransferase 10 (NAT10), a nucleolar protein involved in histone acetylation, is overexpressed in several cancers. We investigated whether NAT10 is involved in doxorubicin resistance in BC and explored the potential mechanisms. Remodelin, a NAT10 inhibitor, and a NAT10 small interfering RNA (siRNA) were used to inhibit NAT10; both remodelin and the NAT10 siRNA reduced cell viability and attenuated doxorubicin resistance in four BC cell lines. Remodelin and doxorubicin synergistically reduced cell viability, though knockdown of NAT10 and remodelin did not exert a synergistic effect in doxorubicin-treated cells. Remodelin upregulated E-cadherin and downregulated vimentin, canonical markers of the epithelial-mesenchymal transition (EMT), whereas doxorubicin had the opposite effects. Moreover, both remodelin and knockdown of NAT10 reversed the doxorubicin-induced EMT. Finally, when the EMT was blocked using a siRNA targeting Twist, remodelin could not alleviate doxorubicin resistance. Collectively, these findings demonstrate that inhibition of NAT10 attenuates doxorubicin resistance by reversing the EMT in BC. This represents a novel mechanism of doxorubicin resistance in BC and indicates remodelin may have potential clinical value to increase the efficacy of doxorubicin-based chemotherapy in BC.