Clinical and Translational Research Center at Shanghai First Maternity & Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.
Mol Cell Biochem. 2012 Feb;361(1-2):39-45. doi: 10.1007/s11010-011-1085-x. Epub 2011 Sep 30.
Cell migration plays major roles in human breast cancer-related death, but the molecular mechanisms remain unclear. Valproic acid (VPA) is a broad-spectrum inhibitor of class I and II histone deacetylases and shows great anticancer activity in a variety of human cancers including breast cancer. In this study, we found that VPA significantly inhibited cell migration but not proliferation of human breast cancer MDA-MB-231 cells. Mechanistic studies found that VPA significantly inhibited the expression of Survivin. Knockdown of Survivin could obviously inhibited cell migration, while over-expression of Survivin markedly rescued the inhibition of VPA on cell migration. Further studies found that knockdown of HDAC2 completely mimicked the effects of VPA on Survivin and cell migration, and over-expression of Survivin could also rescue the effects of HDAC2 knockdown on cell migration. Collectively, these results indicated that HDAC2 may be the specific target of VPA in breast cancer cells, and specific inhibition of HDAC2, especially by small molecular chemicals may lead to less side-effects and provide a better strategy than VPA application for human breast cancer treatment.
细胞迁移在人类乳腺癌相关死亡中起着重要作用，但分子机制仍不清楚。丙戊酸（VPA）是 I 类和 II 类组蛋白去乙酰化酶的广谱抑制剂，在多种人类癌症中显示出强大的抗癌活性，包括乳腺癌。在这项研究中，我们发现 VPA 显著抑制了人乳腺癌 MDA-MB-231 细胞的迁移，但不抑制增殖。机制研究发现 VPA 显著抑制了 Survivin 的表达。Survivin 的敲低明显抑制了细胞迁移，而 Survivin 的过表达则显著挽救了 VPA 对细胞迁移的抑制作用。进一步的研究发现，HDAC2 的敲低完全模拟了 VPA 对 Survivin 和细胞迁移的作用，而 Survivin 的过表达也可以挽救 HDAC2 敲低对细胞迁移的作用。综上所述，这些结果表明 HDAC2 可能是 VPA 在乳腺癌细胞中的特定靶标，而特定抑制 HDAC2，特别是通过小分子化学物质，可能会产生较少的副作用，并为人类乳腺癌治疗提供比 VPA 应用更好的策略。
