The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China.
Cell Death Dis. 2013 Sep 19;4(9):e811. doi: 10.1038/cddis.2013.333.
Prostate cancer is one of the most frequently diagnosed cancers among men. Dietary intake of nutrients is considered crucial for preventing the initiation of events leading to the development of carcinoma. Many dietary compounds have been considered to contribute to cancer prevention including zinc, which has a pivotal role in modulating apoptosis. However, the mechanism for zinc-mediated prostate cancer chemoprevention remains enigmatic. In this study, we investigated the therapeutic effect of zinc in prostate cancer chemoprevention for the first time. Exposure to zinc induced apoptosis and resulted in transactivation of p21(WAF1/Cip1) in a Smad-dependent and p53-independent manner in prostate cancer cells. Smad2 and PIAS1 proteins were significantly upregulated resulting in dramatically increased interactions between Smad2/4 and PIAS1 in the presence of zinc in LNCaP cells. Furthermore, it was found that the zinc-induced Smad4/2/PIAS1 transcriptional complex is responsible for Smad4 binding to SBE1 and SBE3 regions within the p21(WAF1/Cip1) promoter. Exogenous expression of Smad2/4 and PIAS1 promotes zinc-induced apoptosis concomitant with Smad4 nuclear translocation, whereas endogenous Smad2/4 silencing inhibited zinc-induced apoptosis accompanying apparent p21(WAF1/Cip1) reduction. Moreover, the knockdown of PIAS1 expression attenuated the zinc-induced recruitment of Smad4 on the p21(WAF1/Cip1) promoter. The colony formation experiments demonstrate that PIAS1 and Smad2/4 silencing could attenuate zinc apoptotic effects, with a proliferation of promoting effects. We further demonstrate the correlation of apoptotic sensitivity to zinc and Smad4 and PIAS1 in multiple cancer cell lines, demonstrating that the important roles of PIAS1, Smad2, and Smad4 in zinc-induced cell death and p21(WAF1/Cip1) transactivation were common biological events in different cancer cell lines. Our results suggest a new avenue for regulation of zinc-induced apoptosis, and provide a model that demonstrates zinc endorses the Smad2/4/PIAS1 complex to activate the p21(WAF1/Cip1) gene that mediates apoptosis.
前列腺癌是男性中最常见的癌症之一。人们认为，营养物质的饮食摄入对于预防导致癌发生的事件的启动至关重要。许多饮食化合物被认为有助于预防癌症，包括锌，锌在调节细胞凋亡中起着关键作用。然而，锌介导的前列腺癌化学预防的机制仍然是个谜。在这项研究中，我们首次研究了锌在前列腺癌化学预防中的治疗作用。锌暴露以 Smad 依赖性和 p53 非依赖性方式诱导前列腺癌细胞凋亡，并导致 p21(WAF1/Cip1)的反式激活。锌存在时，LNCaP 细胞中的 Smad2 和 PIAS1 蛋白显著上调，导致 Smad2/4 与 PIAS1 之间的相互作用显著增加。此外，发现锌诱导的 Smad4/2/PIAS1 转录复合物负责 Smad4 与 p21(WAF1/Cip1)启动子内 SBE1 和 SBE3 区域的结合。外源性表达 Smad2/4 和 PIAS1 促进锌诱导的凋亡，同时伴有 Smad4 核转位，而内源性 Smad2/4 沉默抑制锌诱导的凋亡，同时伴有明显的 p21(WAF1/Cip1)减少。此外，PIAS1 表达的敲低减弱了锌诱导的 Smad4 在 p21(WAF1/Cip1)启动子上的募集。集落形成实验表明，PIAS1 和 Smad2/4 的沉默可减弱锌的凋亡作用，具有促进增殖的作用。我们进一步证明了在多种癌细胞系中凋亡对锌的敏感性与 Smad4 和 PIAS1 之间的相关性，表明 PIAS1、Smad2 和 Smad4 在锌诱导的细胞死亡和 p21(WAF1/Cip1)反式激活中的重要作用是不同癌细胞系中的共同生物学事件。我们的结果为调节锌诱导的细胞凋亡提供了新的途径，并提供了一个模型，证明锌支持 Smad2/4/PIAS1 复合物激活介导凋亡的 p21(WAF1/Cip1)基因。
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