Abstract

Triple-negative breast cancer (TNBC) is associated with an increased risk of metastasis and a poor prognosis. The invasive ability of TNBC relies on actin reorganization and is regulated by histone deacetylase 6 (HDAC6). The present study aimed to examine the effect of MPT0G211, a novel HDAC6 inhibitor, on cell migration and microtubule association in both in vitro and in vivo models of TNBC. Here MPT0G211 more selectively and potently targeted and inhibited HDAC6, compared with tubastatin A, another selective HDAC6 inhibitor. In vitro, MPT0G211 decreased the migration of the TNBC cell line MDA-MB-231, particularly when administered together with paclitaxel, and increased heat shock protein 90 (Hsp90) acetylation, leading to the dissociation of Hsp90 from aurora-A and proteasomal degradation. Furthermore, MPT0G211 significantly disrupted F-actin polymerization by increasing cortactin acetylation and downregulating slingshot protein phosphatase 1 (SSH1) and active cofilin expression. In vivo, MPT0G211 treatment significantly ameliorated TNBC metastasis. In conclusion, our results demonstrate that MPT0G211 reduces TNBC cell motility by promoting cortactin acetylation and aurora-A degradation, and inhibiting the cofilin–F-actin pathway via HDAC6 activity attenuation. MPT0G211 therefore demonstrates therapeutic potential for invasive TNBC.

Original languageEnglish
Pages (from-to)992-1003
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1866
Issue number6
DOIs
Publication statusPublished - Jun 1 2019

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Triple Negative Breast Neoplasms
Histone Deacetylase Inhibitors
Breast Neoplasms
Histone Deacetylases
Acetylation
Cortactin
HSP90 Heat-Shock Proteins
Actins
Cell Movement
Actin Depolymerizing Factors
Neoplasm Metastasis
Protein Phosphatase 1
Paclitaxel
In Vitro Techniques
Microtubules
Polymerization
Down-Regulation
Cell Line

Keywords

  • Aurora-A
  • Cell migration
  • F-actin
  • Histone deacetylase 6
  • Paclitaxel
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Anti-metastatic activity of MPT0G211, a novel HDAC6 inhibitor, in human breast cancer cells in vitro and in vivo. / Hsieh, Yi Ling; Tu, Huang Ju; Pan, Shiow Lin; Liou, Jing Ping; Yang, Chia Ron.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1866, No. 6, 01.06.2019, p. 992-1003.

Research output: Contribution to journalArticle

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abstract = "Triple-negative breast cancer (TNBC) is associated with an increased risk of metastasis and a poor prognosis. The invasive ability of TNBC relies on actin reorganization and is regulated by histone deacetylase 6 (HDAC6). The present study aimed to examine the effect of MPT0G211, a novel HDAC6 inhibitor, on cell migration and microtubule association in both in vitro and in vivo models of TNBC. Here MPT0G211 more selectively and potently targeted and inhibited HDAC6, compared with tubastatin A, another selective HDAC6 inhibitor. In vitro, MPT0G211 decreased the migration of the TNBC cell line MDA-MB-231, particularly when administered together with paclitaxel, and increased heat shock protein 90 (Hsp90) acetylation, leading to the dissociation of Hsp90 from aurora-A and proteasomal degradation. Furthermore, MPT0G211 significantly disrupted F-actin polymerization by increasing cortactin acetylation and downregulating slingshot protein phosphatase 1 (SSH1) and active cofilin expression. In vivo, MPT0G211 treatment significantly ameliorated TNBC metastasis. In conclusion, our results demonstrate that MPT0G211 reduces TNBC cell motility by promoting cortactin acetylation and aurora-A degradation, and inhibiting the cofilin–F-actin pathway via HDAC6 activity attenuation. MPT0G211 therefore demonstrates therapeutic potential for invasive TNBC.",
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AU - Liou, Jing Ping

AU - Yang, Chia Ron

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