Zebularine-induced reduction in VEGF secretion by HIF-1α degradation in oral squamous cell carcinoma.
Zebularine-induced reduction in VEGF secretion by HIF-1α degradation in oral squamous cell carcinoma.
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DOI：
10.3892/mmr.1.4.465
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发表时间：
2008-07
影响因子：
3.4
通讯作者：
Maiko Suzuki;F. Shinohara;H. Rikiishi
中科院分区：
文献类型：
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作者：
Maiko Suzuki;F. Shinohara;H. Rikiishi
血管内皮生长因子（VEGF）是口腔鳞状细胞癌（OSCC）血管生成的有效诱导因子。在这项研究中，我们使用了新的DNA甲基转移酶抑制剂zebularine（Zeb），以调查表观遗传的影响，分泌VEGF-A的OSCC细胞系HSC-3。在常氧条件下，我们发现Zeb通过降低缺氧诱导因子-1 α（HIF-1α）的活性以剂量依赖的方式抑制分泌。用蛋白酶体抑制剂MG 132处理细胞可以保护HIF-1α蛋白免受Zeb介导的表观遗传调控。此外，我们的研究表明，无论是PI 3 K/Akt还是p53信号通路都不是Zeb诱导的HIF-1α降解所必需的。简而言之，Zeb在常氧条件下影响HSC-3细胞中HIF-1α蛋白的稳定性及其靶点（如VEGF）的活性。这项研究为一种新的抗癌方法奠定了基础，这种方法可能会在分子分期中找到应用。
Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis in oral squamous cell carcinoma (OSCC). In this study, we used the novel DNA methyltransferase inhibitor zebularine (Zeb) to investigate epigenetic influences on the secretion of VEGF-A in the OSCC cell line HSC-3. Under normoxic conditions, we found that Zeb inhibited secretion in a dose-dependent manner by reducing the activity of hypoxia-inducible factor-1α (HIF-1α). Treatment of the cells with the proteasome inhibitor MG132 protected the HIF-1α protein from Zeb-mediated epigenetic regulation. In addition, our study revealed that neither the PI3K/Akt nor the p53 signaling pathway is required for Zeb-induced HIF-1α degradation. In short, Zeb influenced the stability of the HIF-1α protein and the activity of its targets, such as VEGF, in HSC-3 cells in normoxic conditions. This study has laid the foundation for a novel anti-cancer approach, which may find applications in molecular staging.