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

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Abstract

Purpose

Improved prognosis for triple-negative breast cancer (TNBC) has 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 an HDAC inhibitor was tested in 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 for TNBC cells and immunohistochemical analyses for clinical specimens obtained from breast cancer patients who were treated with eribulin.

Results

The simultaneous administration of low concentrations (0.2 μM) of VOR or RICO enhanced the anti-tumor effect of eribulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. Meanwhile, pretreatment with 5 μM of VOR or RICO enhanced eribulin sensitivity in all three cell lines. Low concentration of VOR or RICO increased acetylated α-tubulin expression in MDA-MB-231 and Hs578T cells. In contrast, whereas 5 μM of VOR or RICO increased the expression of acetylated α-tubulin in MDA-MB-157 cells, low concentrations did not. Eribulin 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. Immunohistochemical analyses revealed that 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.

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Data availability

The data supporting the findings of this work are available from the authors upon reasonable request.

Abbreviations

EMT:

Epithelial–mesenchymal transition

ER:

Estrogen receptor

FEC:

5FU, epirubicin and cyclophosphamide

HDAC:

Histone deacetylase

MET:

Mesenchymal–epithelial transition

PR:

Partial response

RICO:

Ricolinostat

siRNA:

Small interfering RNA

TME:

Tumor microenvironment

TNBC:

Triple-negative breast cancer

VOR:

Vorinostat

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Acknowledgement

We would like to thank Editage (www.editage.com) for English language editing.

Funding

This work was supported by Grants-in-aid for Scientific Research (#17K10541) from the Japanese Society for the Promotion of Science.

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Authors and Affiliations

  1. Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-861, Japan

    Takaaki Oba, Mayu Ono & Ken-ichi Ito

  2. Department of Laboratory Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan

    Hisanori Matoba & Takeshi Uehara

  3. Department of Breast Surgery, Horosaki Municipal Hospital, 3-8-1 Omachi, Hirosaki, Japan

    Yoshie Hasegawa

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  1. Takaaki Oba
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Contributions

TO and KI contributed to the conception and design of the experiments, data analysis, and interpretation and drafted the manuscript. TO, MO, and YH performed the experiments and contributed to the acquisition of data. MH and TU evaluated the IHC staining of acetylated α-tubulin. All authors read and approved the final manuscript.

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Correspondence to Ken-ichi Ito.

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This study was approved by the Medical Ethics Committee on Clinical Investigation of Shinshu University (No. 3819). All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Oba, T., Ono, M., Matoba, H. et al. HDAC6 inhibition enhances the anti-tumor effect of eribulin through tubulin acetylation in triple-negative breast cancer cells. Breast Cancer Res Treat 186, 37–51 (2021). https://doi.org/10.1007/s10549-020-06033-2

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