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  • br Yi Ling Hsieha Huang Ju

    2020-08-12


    Yi-Ling Hsieha,1, Huang-Ju Tua,b,1, Shiow-Lin Panc,d,e, Jing-Ping Lioub, Chia-Ron Yanga,
    a School of Pharmacy, College of Medicine, National Taiwan University, No. 33, Linsen S. Road, Taipei 10050, Taiwan
    b School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wuxing Street, Taipei 11031, Taiwan
    c Ph.D Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
    d Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
    e TMU Biomedical Commercialization Center, Taipei Medical University, Taipei 11031, Taiwan
    Keywords:
    Triple-negative breast cancer
    Cell migration
    Histone deacetylase 6
    Aurora-A
    F-actin
    Paclitaxel 
    Triple-negative breast cancer (TNBC) is associated with an increased risk of metastasis and a poor prognosis. The invasive ability of TNBC relies on DAPI 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 mi-crotubule 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 to-gether 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 con-clusion, 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.
    1. Introduction disease, accounting for more than half of all breast cancer deaths [5].
    Therefore, novel treatments that target critical intracellular molecules Breast cancer is among the five most common cancers worldwide. in TNBC are required. Currently, the majority of deaths in affected patients are caused by Epigenetic modification is defined as changes in gene activity and
    metastases of breast cancer [1,2]. Typically, breast cancers are classi- expression in the absence of DNA sequence alterations [6]. This process fied into one of three major types. Estrogen receptor-positive cancers, is mainly regulated by the enzymes histone acetyltransferases (HATs)
    which are most common, can be cured using hormonal therapy agents, and histone deacetylases (HDACs), which respectively execute the
    such as tamoxifen [3]. Tumors that overexpress the receptor tyrosine acetylation and deacetylation of lysine residues at the amino terminals kinase HER2 but lack estrogen receptor expression can be treated effi- of histone or non-histone proteins [7]. Relevant studies have shown the ciently with antibodies specific for HER2 (e.g., trastuzumab) [4]. The regulation of epigenetic modification is highly important to tumor-
    third and relatively less common type is described as triple-negative igenesis and cancer progression [7,8]. Accordingly, HDAC inhibition
    breast cancer (TNBC), given the negative of the estrogen and proges- has elicited much interest in terms of cancer therapeutics. Currently,
    terone receptors and HER2. As these tumors do not respond to hor- four HDAC inhibitors (vorinostat, romidepsin, belinostat, and panobi- monal or HER2 antibody-mediated therapies, general chemother- nostat) have been approved for the treatment of different kind of can-
    apeutic agents remain the only option for patients with TNBC. Given cers such as cutaneous T-cell lymphoma, peripheral T-cell lymphoma,
    this absence of targeted therapies and a tendency toward rapid pro- and multiple myeloma [9]. However, these drugs are associated with gression to metastasis, TNBC is considered the deadliest form of the several side effects, including gastrointestinal symptoms (e.g.,
    Corresponding author.
    E-mail address: [email protected] (C.-R. Yang). 1 Yi-Ling Hsieh and Huang-Ju Tu contributed equally to this work.
    (caption on next page)
    Fig. 1. MPT0G211 significantly inhibited HDAC6 activity in human breast cancer cells.