Department of Science and Technology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 202032, China.
Molecules. 2013 Dec 4;18(12):14935-47. doi: 10.3390/molecules181214935.
Hepatocarcinogenesis is associated with epigenetic changes, including histone deacetylases (HDACs). Epigenetic modulation by HDAC inhibition is a potentially valuable approach for hepatocellular carcinoma treatment. In present study, we evaluated the anticancer effects of sodium valproate (SVP), a known HDAC inhibitor, in human hepatocarcinoma cells. The results showed SVP inhibited the proliferation of Bel-7402 cells in a dose-dependent manner. Low dose SVP treatment caused a large and flat morphology change, positive SA-β-gal staining, and G0/G1 phase cell cycle arrest in human hepatocarcinoma cells. Low dose SVP treatment also increased acetylation of histone H3 and H4 on p21 promoter, accompanied by up-regulation of p21 and down-regulation of RB phosphorylation. These observations suggested that a low dose of SVP could induce cell senescence in hepatocarcinoma cells, which might correlate with hyperacetylation of histone H3 and H4, up-regulation of p21, and inhibition of RB phosphorylation. Since the effective concentration inducing cell senescence in hepatocarcinoma cells is clinically available, whether a clinical dose of SVP could induce cell senescence in clinical hepatocarcinoma is worthy of further study.
肝癌的发生与表观遗传改变有关，包括组蛋白去乙酰化酶（HDACs）。HDAC 抑制的表观遗传调节是治疗肝细胞癌的一种有潜在价值的方法。在本研究中，我们评估了已知的 HDAC 抑制剂丙戊酸钠（SVP）对人肝癌细胞的抗癌作用。结果表明，SVP 以剂量依赖性方式抑制 Bel-7402 细胞的增殖。低剂量 SVP 处理导致人肝癌细胞发生大而扁平的形态变化，SA-β-gal 染色阳性，细胞周期 G0/G1 期阻滞。低剂量 SVP 处理还增加了 p21 启动子上组蛋白 H3 和 H4 的乙酰化，同时上调了 p21，下调了 RB 的磷酸化。这些观察结果表明，低剂量 SVP 可诱导肝癌细胞衰老，这可能与组蛋白 H3 和 H4 的过度乙酰化、p21 的上调和 RB 磷酸化的抑制有关。由于诱导肝癌细胞衰老的有效浓度在临床上是可用的，因此 SVP 的临床剂量是否能诱导临床肝癌细胞衰老值得进一步研究。
