Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Cell Death Dis. 2010 May 20;1(5):e44. doi: 10.1038/cddis.2010.21.
Histone deacetylases (HDACs) are epigenetic regulators that are important for the control of various pathophysiological events. We found that HDAC inhibitors completely abolished transforming growth factor-β1 (TGF-β1)-induced apoptosis in AML-12 and primary mouse hepatocytes. Expression of a dominant-negative mutant of HDAC1 or downregulation of HDAC1 by RNAi both suppressed TGF-β1-induced apoptosis. In addition, overexpression of HDAC1 enhanced TGF-β1-induced apoptosis, and the rescue of HDAC1 expression in HDAC1 RNAi cells restored the apoptotic response of cells to TGF-β1. These data indicate that HDAC1 functions as a proapoptotic factor in TGF-β1-induced apoptosis. In contrast, downregulation of HDAC2 by RNAi increased spontaneous apoptosis and markedly enhanced TGF-β1-induced apoptosis, suggesting that HDAC2 has a reciprocal role in controlling cell survival. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) by MEK1 inhibitor PD98059 or expression of a kinase-dead mutant of MEK1 restored the apoptotic response to TGF-β1 in HDAC1 RNAi cells. Strikingly, HDAC2 RNAi caused an inhibition of ERK1/2, and the spontaneous apoptosis can be abolished by reactivation of ERK1/2. Taken together, our data demonstrate that HDAC1 and 2 reciprocally affect cell viability by differential regulation of ERK1/2; these observations provide insight into the roles and potential mechanisms of HDAC1 and 2 in apoptosis.
组蛋白去乙酰化酶（HDACs）是表观遗传调节剂，对于控制各种病理生理事件非常重要。我们发现 HDAC 抑制剂完全消除了转化生长因子-β1（TGF-β1）诱导的 AML-12 和原代小鼠肝细胞凋亡。HDAC1 的显性负突变体的表达或 RNAi 下调 HDAC1 均抑制了 TGF-β1 诱导的细胞凋亡。此外，HDAC1 的过表达增强了 TGF-β1 诱导的细胞凋亡，并且在 HDAC1 RNAi 细胞中恢复 HDAC1 表达的挽救恢复了细胞对 TGF-β1 的凋亡反应。这些数据表明 HDAC1 在 TGF-β1 诱导的细胞凋亡中作为促凋亡因子发挥作用。相比之下，通过 RNAi 下调 HDAC2 增加了自发凋亡并显著增强了 TGF-β1 诱导的细胞凋亡，表明 HDAC2 在控制细胞存活方面具有相反的作用。此外，通过 MEK1 抑制剂 PD98059 抑制细胞外信号调节激酶 1/2（ERK1/2）或表达 MEK1 的激酶失活突变体恢复了 HDAC1 RNAi 细胞对 TGF-β1 的凋亡反应。引人注目的是，HDAC2 RNAi 导致 ERK1/2 的抑制，并且通过重新激活 ERK1/2 可以消除自发的细胞凋亡。总之，我们的数据表明 HDAC1 和 2 通过差异调节 ERK1/2 相互影响细胞活力；这些观察结果为 HDAC1 和 2 在凋亡中的作用和潜在机制提供了深入的了解。
