Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation.
Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation.
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DOI：
10.3892/ijo.2015.3213
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发表时间：
2015-12
影响因子：
5.2
通讯作者：
Ohta T
中科院分区：
文献类型：
--
作者：
Mawatari T;Ninomiya I;Inokuchi M;Harada S;Hayashi H;Oyama K;Makino I;Nakagawara H;Miyashita T;Tajima H;Takamura H;Fushida S;Ohta T
乳腺癌在分子水平上包括一组异质性疾病。已知乳腺癌的化学敏感性取决于其分子亚型。我们研究了组蛋白去乙酰化酶（HDAC）抑制剂丙戊酸（VPA）对4种不同分子亚型乳腺癌细胞系的生长抑制作用及其机制。研究了VPA在四种不同乳腺癌细胞系中的生长抑制作用。在VPA敏感、人表皮受体2（HER 2）过表达的SKBR 3细胞中，检测VPA对p21 WAF 1、切割的caspase-3、乙酰化热休克蛋白（Hsp）90、乙酰化Hsp 70和乙酰化α-微管蛋白水平的改变。VPA对乳腺癌细胞株的生长抑制作用具有剂量依赖性和作用时间依赖性。VPA对HER 2过表达SKBR 3细胞系的细胞生长抑制程度远大于其他研究的细胞系。在SKBR 3细胞系中，VPA在早期上调p21 WAF 1的表达并切割caspase-3。VPA以时间依赖性方式显著增加Hsp 70乙酰化，但不增加Hsp 90乙酰化。我们的数据表明，VPA抑制细胞增殖，诱导细胞周期阻滞和HER 2过表达乳腺癌细胞凋亡。这种抗增殖作用可能是VPA作为HDAC抑制剂的直接作用。我们提出了一种替代机制，即Hsp 70的乙酰化破坏了Hsp 90的功能，并导致其客户蛋白的下调，包括HER 2，这可能是VPA的间接功能，在这个意义上，非组蛋白蛋白被乙酰化。
Breast cancer encompasses a heterogeneous group of diseases at the molecular level. It is known that chemo-sensitivity of breast cancer depends on its molecular subtype. We investigated the growth inhibitory effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, and the mechanism of this inhibition on four breast cancer cell lines with different molecular subtypes. The growth inhibitory effect of VPA in the four different breast cancer cell lines was investigated. The alteration of levels of p21 WAF1, cleaved caspase-3, acetylated Heat shock protein (Hsp) 90, acetylated Hsp70, and acetylated α-tubulin by VPA was examined in VPA-sensitive, human epidermal receptor 2 (HER2)-overexpressing SKBR3 cells. The cell growth inhibition of breast cancer cell lines was dependent on the dose and exposure time of VPA. The cell growth of HER2-overexpressing SKBR3 cell line was inhibited by VPA to a much greater degree than other cell lines studied. In SKBR3 cell line, VPA upregulated expression of p21 WAF1 and cleaved caspase-3 in the early phase. VPA markedly increased Hsp70 acetylation in a time-dependent manner but did not increase Hsp90 acetylation. Our data demonstrated that VPA inhibited cell proliferation and induced cell cycle arrest and apoptosis of HER2-overexpressing breast cancer cells. This anti-proliferation effect might be the direct function of VPA as an HDAC inhibitor. We propose an alternative mechanism whereby acetylation of Hsp70 disrupts the function of Hsp90 and leads to downregulation of its client proteins, including HER2 that might be the indirect function of VPA, in the sense that non-histone proteins are acetylated.