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Valproic Acid Inhibits Proliferation of HER2-Expressing Breast Cancer Cells by Inducing Cell Cycle Arrest and Apoptosis Through Hsp70 Acetylation

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Valproic Acid Inhibits Proliferation of HER2-Expressing Breast Cancer Cells by Inducing Cell Cycle Arrest and Apoptosis Through Hsp70 Acetylation INTERNATIONAL JOURNAL OF ONCOLOGY 47: 2073-2081, 2015 Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation TOSHIKI Mawatari1, Itasu Ninomiya1, MASAFUMI INOKUCHI2, SHINICHI HARADA3, HIRONORI Hayashi1, Katsunobu Oyama1, ISAMU MAKINO1, Hisatoshi Nakagawara1, TOMOHARU Miyashita1, HIDEHIRO TAJIMA1, HIROYUKI TAKAMURA1, SACHIO FUSHIDA1 and TETSUO Ohta1 1Gastroenterologic Surgery, Division of Cancer Medicine, 2Breast Oncology, Division of Cancer Medicine, 3Center for Biomedical Research and Education, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan Received July 28, 2015; Accepted September 16, 2015 DOI: 10.3892/ijo.2015.3213 Abstract. Breast cancer encompasses a heterogeneous group cleaved caspase-3 in the early phase. VPA markedly increased of diseases at the molecular level. It is known that chemo- Hsp70 acetylation in a time-dependent manner but did not sensitivity of breast cancer depends on its molecular subtype. increase Hsp90 acetylation. Our data demonstrated that VPA We investigated the growth inhibitory effect of valproic inhibited cell proliferation and induced cell cycle arrest and acid (VPA), a histone deacetylase (HDAC) inhibitor, and apoptosis of HER2-overexpressing breast cancer cells. This the mechanism of this inhibition on four breast cancer cell anti-proliferation effect might be the direct function of VPA lines with different molecular subtypes. The growth inhibi- as an HDAC inhibitor. We propose an alternative mechanism tory effect of VPA in the four different breast cancer cell whereby acetylation of Hsp70 disrupts the function of Hsp90 lines was investigated. The alteration of levels of p21 WAF1, and leads to downregulation of its client proteins, including cleaved caspase-3, acetylated Heat shock protein (Hsp) 90, HER2 that might be the indirect function of VPA, in the sense acetylated Hsp70, and acetylated α-tubulin by VPA was that non-histone proteins are acetylated. examined in VPA-sensitive, human epidermal receptor 2 (HER2)-overexpressing SKBR3 cells. The cell growth Introduction inhibition of breast cancer cell lines was dependent on the dose and exposure time of VPA. The cell growth of HER2- Breast cancer is one of the most common cancers in women. overexpressing SKBR3 cell line was inhibited by VPA to a In recent years, major advances in breast cancer therapy have much greater degree than other cell lines studied. In SKBR3 been achieved. Nevertheless, because cancer cells may present cell line, VPA upregulated expression of p21 WAF1 and a number of resistance mechanisms reducing the effectiveness of chemotherapeutic drugs, new and more effective strategies for treatment and prevention are still much needed. Breast cancer encompasses a heterogeneous group of diseases at the Correspondence to: Dr Masafumi Inokuchi, Breast Oncology, molecular level and can be classified into at least five distinct Division of Cancer Medicine, Graduate School of Medical Science, subtypes by gene-expression profiling: luminal A, luminal B, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa normal breast-like, human epidermal receptor 2 (HER2), and 920-8641, Japan basal-like. Recent studies based on neoadjuvant clinical trials E-mail: [email protected] for breast cancer suggested that chemosensitivity depends on its molecular subtype (1). Abbreviations: VPA, valproic acid; HDAC, histone deacetylase; There is increasing evidence that epigenetic alterations, Hsp, heat shock protein; HER2, human epidermal receptor 2; such as histone acetylation and promoter methylation, play HAT, histone acetyltransferase; ATP, adenosine triphosphate; ADP, adenosine diphosphate; TSA, trichostatin A; ER, estrogen receptor; important roles in regulation of gene expression associated RIPA, radio-immunoprecipitation; TUNEL, TdT-mediated dUTP with the cell cycle and apoptosis (2). Chromatin remodeling nick-end labeling; CBZ, carbamazepine regulates gene transcription and is in turn regulated by two enzymes, histone acetyltransferase (HAT) and histone Key words: valproic acid, HDAC inhibitor, Hsp70, Hsp90, breast deacetylase (HDAC), that control post-translational modifica- cancer, HER2 tions of histones. Acetylation of lysine residues on the histones weakens their binding to DNA and induces a change in DNA conformation and allows transcription factors to bind to the promoter regions of target genes (3,4). 2074 Mawatari et al: Valproic acid inhibits proliferation of HER2-EXpressing breast cancer cells In mammalian cells, there are 18 different HDACs, which cells (13). However, as a class I HDAC inhibitor, VPA has only can be further divided into four types. HDAC 1, 2, 3, and 8 a weak effect on inhibition of HDAC6 (14,28). are class I deacetylases that localize almost exclusively to It is known that Hsp70 is required for the assembly of the the nucleus and are ubiquitously expressed in various human signaling protein-Hsp90 heterocomplex. Hsp90 is involved cell lines and tissues. HDAC 4, 5, 6, 7, 9, and 10 are class II in two multi-chaperone complexes and promotes correct deacetylases, which shuttle between the nucleus and cyto- folding or degradation of client proteins, depending on its plasm with certain cellular signals. Class III comprises the conformation. When adenosine triphosphate (ATP) is bound conserved nicotinamide adenine dinucleotide-dependent Sir2 to the amino-terminal nucleotide-binding pocket, Hsp90 is family of deacetylases. HDAC11 is the only member of the associated with co-chaperone proteins p23 and p50Cdc37 class IV HDACs (5). Aberrant levels of HDAC activity have and directly binds to the client protein to stabilize the interac- been found in a variety of human malignancies and result tions. When adenosine diphosphate (ADP) is bound, Hsp90 is in repression of tumor-suppressor genes and promotion of assembled into the complex with co-chaperone proteins Hsp70 tumorigenesis (6). and p60Hop. Within the complex, Hsp70 directly interacts with Valproic acid (VPA), which has long been used clinically the client protein to promote ubiquitination and degradation for treatment of epilepsy and bipolar disorder without signifi- (25,29). Therefore, the function of Hsp70 may indirectly affect cant toxicity, causes hyperacetylation of the N-terminal tails the chaperone function of Hsp90. However, it is unknown of histones H3 and H4 in vitro and in vivo and inhibits HDAC whether VPA can influence the chaperone function of Hsp70 activity, probably by binding to the catalytic center and, and the Hsp90 in breast cancer cells. We speculate that VPA thereby, blocking substrate access (7,8). VPA inhibits both could enhance the acetylation of Hsp70 and Hsp90 through its class I and II HDACs, with high potency for class I HDACs (9). inhibitory effect on HDAC6. Earlier studies indicated that p21 WAF1, one of the target In this study, we investigated both inhibitory and pro- genes induced by VPA, affects differentiation and decreases apoptotic effects of VPA on breast cancer cell lines with tumor cell growth (10,11). Another report focused on the various molecular subtypes. In addition, we explored whether apoptotic activity of VPA (12). However, the detailed mecha- VPA enhanced the acetylation of Hsp70 and Hsp90 and its nism of apoptosis induced by VPA has not been elucidated. In contribution to tumor growth inhibition in the VPA-sensitive addition, recent evidence suggests that HDAC inhibitors also cell line. enhance the acetylation of non-histone proteins, such as p53, c-Jun, and α-tubulin (13-15). Materials and methods Although VPA has been shown to reduce cancer prolifera- tion to some extent, there is insufficient amount of data on its Materials. VPA and trichostatin A (TSA) was purchased from effect in breast cancer cells. Studies on the specificity of VPA Sigma-Aldrich Co. (St. Louis, MO, USA). against breast cancer subtypes have often yielded contrasting results and conflicting conclusions (16-18). Cell lines and cell culture. Two cancer cell lines derived Several studies have found that inhibition of HDAC from human breast cancer, estrogen receptor (ER)-positive increases acetylation levels of the core histones as well as and HER2-negative MCF7 cells and ER-negative and some non-histone proteins (13,19), raising the possibility that HER2-overexpressing SKBR3 cells were provided by the transcription-independent effects of HDAC inhibitors are also Cell Resource Center for Biomedical Research, Institute of important for their anticancer activity (5). It has recently been Development, Aging and Cancer, Tohoku University. The other reported that pan-HDAC inhibitors such as LAQ824, LBH589, two cell lines derived from human breast cancer, ER-negative and SAHA exert their antitumor activity by inhibition of and HER2-negative MDA-MB-231 cells and ER-positive and HDAC6, a deacetylase of α-tubulin and heat shock protein HER2-overexpressing BT474 cells, were purchased from the (Hsp) 90 (19-21). The inhibition of HDAC6 results in acetyla- American Type Culture Collection (Rockville, MD, USA). tion of Hsp90 and disruption of its chaperone function (21-23). These breast cancer cells were seeded in 75-cm2 dishes Heat shock proteins (Hsps) are a group of highly conserved (Becton-Dickinson, Franklin Lakes, NJ, USA) and cultured molecular chaperones which were originally identified by their in 10 ml of medium at 37˚C in a humidified atmosphere of induction in response to cellular stresses. Hsps are classified 5% CO2.
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