HDAC6 inhibition enhances the anti-tumor effect of eribulin through tubulin acetylation in triple negative breast cancer cells

Abstract Background: Improved prognosis for triple-negative breast cancer (TNBC) has currently plateaued and the development of novel therapeutic strategies is required. This study aimed to explore the anti-tumor effect of combined eribulin and HDAC inhibitor (vorinostat: VOR, pan-HDAC inhibitor and ricolinostat: RICO, selective HDAC6 inhibitor) treatment for TNBC. Methods: The effect of eribulin in combination with VOR or RICO was tested based on both concurrent and sequential administration to three TNBC cell lines (MDA-MB-231, Hs578T, and MDA-MB-157) and their eribulin-resistant derivatives. The expression of acetylated α-tubulin was analyzed by western blotting. Immunohistochemical analyses of clinical specimens obtained from breast cancer patients who underwent neoadjuvant chemotherapy with eribulin were also examined. Results: The simultaneous administration of low concentrations of VOR (0.2 μM) or RICO (0.2 μM) enhanced the anti-tumor effect of eribulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. Meanwhile, pre-treatment with 5 μM of VOR or RICO enhanced sensitivity to eribulin in MDA-MB-231, Hs578T, and MDA-MB-157 cells. VOR or RICO increased acetylated α-tubulin expression in MDA-MB-231 and Hs578T cells in a dose-dependent manner (0.2 μM to 5 μM). In contrast, whereas 5 μM of VOR or RICO increased the expression of acetylated α-tubulin in MDA-MB-157 cells, low concentrations (0.2 μM or 0.5 μM) did not. Treatment with eribulin also increased the expression of acetylated α-tubulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. These phenomena were also observed in eribulin-resistant cells. Based on immunohistochemical analyses of clinical specimens, the expression of acetylated α-tubulin was increased after eribulin treatment in TNBC. Conclusions: HDAC6 inhibition enhances the anti-tumor effect of eribulin through the acetylation of α-tubulin. This combination therapy could represent a novel therapeutic strategy for TNBC.