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  • Nigericin br Therefore novel treatments that target critical intracellular


    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 Nigericin 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.
    (A) The structure of MPT0G211. (B) The human triple-negative breast cancer cell line MDA-MB-231 and estrogen receptor-positive breast cancer cell line MCF-7 (1 × 106) were incubated with or without MPT0G211 or tubastatin A (10 μM) for indicated periods. (C) MDA-MB-231 and MCF-7 cells were treated with MPT0G211, tubastatin A or SAHA (0.1–10 μM) for 24 h, after which whole-cell extracts were subjected to western blotting for the indicated proteins. Acetyl-α-tubulin and acetyl-histone H3 levels in western blots were determined using ImageQuant (Molecular Dynamics, USA). The results are shown as means ± standard errors of the means from three independent experiments. *p < 0.05, **p < 0.01, and ***p < 0.001 compared with the control group.
    diarrhea), thrombocytopenia, and anorexia [10]. The further finding that pan-HDAC inhibitors can augment chemotherapy-induced DNA damage in cardiomyocytes [11] highlights the need to identify more selective inhibitors.
    The HDAC family comprises four classes (I, II, III, and IV) in which isoforms grouped according to their homology to yeast histone deace-tylases and localization within cells [7,12]. The isoform HDAC6 loca-lizes predominantly to the cytoplasm, where it modulates the acetyla-tion of non-histone proteins, including transcription factors (such as p53, FOXP3), heat shock protein 90 (Hsp90), tubulin, and cortactin [13,14]. In a recent study by Rey et al., HDAC6 was identified as an important regulator of cytoskeletal remodeling and cell migration and a required element for two-dimensional matrix proteolysis through ex-periments involving the small interfering RNA-mediated silencing of protein expression in the highly invasive TNBC cell line MDA-MB-231 [15]. In another mechanistic study, HDAC6 was shown to regulate actin and/or microtubule dynamics by deacetylating cortactin, which in turn affects lamellipodia formation or focal adhesion [16]. Furthermore, mice lacking HDAC6 develop normally but exhibit greatly elevated levels of tubulin acetylation in multiple organs [17].