Histone deacetylase inhibitor, trichostatin A induces ubiquitin-dependent cyclin D1 degradation in MCF-7 breast cancer cells.
Histone deacetylase inhibitor, trichostatin A induces ubiquitin-dependent cyclin D1 degradation in MCF-7 breast cancer cells.
复制标题
组蛋白脱乙酰基酶抑制剂trichostatin A在MCF-7乳腺癌细胞中诱导泛素依赖性细胞周期蛋白D1降解。
DOI：
10.1186/1476-4598-5-8
复制
发表时间：
2006-02-20
期刊：
影响因子：
37.3
通讯作者：
Vigushin, David M
中科院分区：
文献类型：
--
作者：
Alao, John P;Stavropoulou, Alexandra V;Lam, Eric W-F;Coombes, R Charles;Vigushin, David M
Cyclin D1 是 G1-S 期细胞周期转变的重要调节因子，已被证明对乳腺癌的发展很重要。 GSK3β 磷酸化 Thr-286 上的细胞周期蛋白 D1，从而增强细胞质中细胞周期蛋白的泛素化、核输出和降解。最近的研究结果表明，小分子细胞周期蛋白 D1 消融剂的开发具有临床意义。我们之前已经证明，组蛋白脱乙酰酶抑制剂曲古抑菌素 A (TSA) 在抑制细胞周期蛋白 D1 基因 (CCND1) 转录之前，会在 MCF-7 乳腺癌细胞中诱导细胞周期蛋白 D1 快速泛素依赖性降解。 TSA 处理还导致多泛素化 GFP-细胞周期蛋白 D1 物质的积累，并降低细胞核内重组蛋白的水平。在这里，我们提供了 TSA 诱导的泛素依赖性细胞周期蛋白 D1 降解的进一步证据，并证明 GSK3β 介导的核输出促进了这种活动。我们的观察结果表明，TSA 处理通过 MCF-7 细胞中 GSK3β/CRM1 依赖性核输出/26S 蛋白酶体降解途径导致细胞周期蛋白 D1 降解增强。我们已经证明，MCF-7 细胞中 TSA 诱导的细胞周期蛋白 D1 快速降解需要 GSK3β 介导的 Thr-286 磷酸化和泛素依赖性 26S 蛋白酶体途径。药物诱导的细胞周期蛋白 D1 抑制有助于抑制乳腺癌细胞增殖，并使细胞对 CDK 和 Akt 抑制剂敏感。此外，抗细胞周期蛋白 D1 疗法对于治疗人类乳腺癌可能具有高度特异性。因此，开发强效且有效的细胞周期蛋白 D1 消融剂具有临床意义。我们的研究结果表明，HDAC 抑制剂可能具有作为小分子细胞周期蛋白 D1 消融剂的治疗潜力。
Cyclin D1 is an important regulator of G1-S phase cell cycle transition and has been shown to be important for breast cancer development. GSK3β phosphorylates cyclin D1 on Thr-286, resulting in enhanced ubiquitylation, nuclear export and degradation of the cyclin in the cytoplasm. Recent findings suggest that the development of small-molecule cyclin D1 ablative agents is of clinical relevance. We have previously shown that the histone deacetylase inhibitor trichostatin A (TSA) induces the rapid ubiquitin-dependent degradation of cyclin D1 in MCF-7 breast cancer cells prior to repression of cyclin D1 gene (CCND1) transcription. TSA treatment also resulted in accumulation of polyubiquitylated GFP-cyclin D1 species and reduced levels of the recombinant protein within the nucleus. Here we provide further evidence for TSA-induced ubiquitin-dependent degradation of cyclin D1 and demonstrate that GSK3β-mediated nuclear export facilitates this activity. Our observations suggest that TSA treatment results in enhanced cyclin D1 degradation via the GSK3β/CRM1-dependent nuclear export/26S proteasomal degradation pathway in MCF-7 cells. We have demonstrated that rapid TSA-induced cyclin D1 degradation in MCF-7 cells requires GSK3β-mediated Thr-286 phosphorylation and the ubiquitin-dependent 26S proteasome pathway. Drug induced cyclin D1 repression contributes to the inhibition of breast cancer cell proliferation and can sensitize cells to CDK and Akt inhibitors. In addition, anti-cyclin D1 therapy may be highly specific for treating human breast cancer. The development of potent and effective cyclin D1 ablative agents is therefore of clinical relevance. Our findings suggest that HDAC inhibitors may have therapeutic potential as small-molecule cyclin D1 ablative agents.