2. Academic Validation
  3. Anti-metastatic activity of MPT0G211, a novel HDAC6 inhibitor, in human breast cancer cells in vitro and in vivo

Anti-metastatic activity of MPT0G211, a novel HDAC6 inhibitor, in human breast cancer cells in vitro and in vivo

  • Biochim Biophys Acta Mol Cell Res. 2019 Jun;1866(6):992-1003. doi: 10.1016/j.bbamcr.2019.03.003.
Yi-Ling Hsieh 1,  Huang-Ju Tu 2,  Shiow-Lin Pan 3,  Jing-Ping Liou 4,  Chia-Ron Yang 5
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Medicine, National Taiwan University, No. 33, Linsen S. Road, Taipei 10050, Taiwan.
  • 2 School of Pharmacy, College of Medicine, National Taiwan University, No. 33, Linsen S. Road, Taipei 10050, Taiwan; School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wuxing Street, Taipei 11031, Taiwan.
  • 3 Ph.D Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; TMU Biomedical Commercialization Center, Taipei Medical University, Taipei 11031, Taiwan.
  • 4 School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wuxing Street, Taipei 11031, Taiwan.
  • 5 School of Pharmacy, College of Medicine, National Taiwan University, No. 33, Linsen S. Road, Taipei 10050, Taiwan. Electronic address: cryang@ntu.edu.tw.
PMID: 30867138 DOI: 10.1016/j.bbamcr.2019.03.003
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.

Keywords

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

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