Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
1] Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC [2] Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, ROC.
Oncogene. 2014 May 29;33(22):2938-46. doi: 10.1038/onc.2013.241. Epub 2013 Jun 17.
Deregulation of Shp2, a non-receptor tyrosine phosphatase, causes hyperactivation of extracellular signal-regulated kinase (ERK), leading to growth abnormality. Here, we show that inhibition of RhoA-Dia is sufficient to upregulate ERK activation in epithelial cells. Oncogenic Shp2 expression attenuates RhoA-Dia signaling, by which microtubule (MT) is destabilized with reduced level of acetylation. Either MT stabilization, silencing of histone deacetylase 6 (HDAC6) or enforcing RhoA-Dia signal prevents oncogenic Shp2-induced ERK hyperactivation. We provide evidence that downregulation of RhoA-Dia-EB1 pathway by oncogenic Shp2 leads to HDAC6-mediated reduction in MT acetylation, in turn affecting ERK regulation. In response to serum stimulation, cells expressing wild-type Shp2 display transient ERK activation. In contrast, cells expressing oncogenic Shp2 have prolonged ERK activation. HDAC6 inhibition diminishes sustained activation of ERK and slows down the growth of these cells. Likewise, in human cancer cells, blocking Shp2 increases MT acetylation and decreases ERK phosphorylation, which are reversed by inhibition of Dia. As such, HDAC6 inhibition in these cells also reduces ERK activity. Our findings link MT regulation by HDAC6 to oncogenic Shp2 and ERK regulation, implicating the therapeutic potential of HDAC6 inhibitor in diseases involving Shp2 deregulation.
Shp2 是一种非受体酪氨酸磷酸酶，其失活会导致细胞外信号调节激酶（ERK）过度激活，从而引发生长异常。在此，我们发现 RhoA-Dia 的抑制足以使上皮细胞中的 ERK 激活上调。致癌性 Shp2 表达减弱了 RhoA-Dia 信号，从而使微管（MT）不稳定，乙酰化水平降低。通过稳定 MT、沉默组蛋白去乙酰化酶 6（HDAC6）或增强 RhoA-Dia 信号，均可阻止致癌性 Shp2 诱导的 ERK 过度激活。我们提供的证据表明，致癌性 Shp2 通过下调 RhoA-Dia-EB1 通路导致 HDAC6 介导的 MT 乙酰化减少，进而影响 ERK 调节。在血清刺激下，表达野生型 Shp2 的细胞显示 ERK 的短暂激活。相比之下，表达致癌性 Shp2 的细胞具有持续的 ERK 激活。HDAC6 抑制可减少 ERK 的持续激活并减缓这些细胞的生长。同样，在人类癌细胞中，阻断 Shp2 会增加 MT 乙酰化并减少 ERK 磷酸化，而 Dia 的抑制可逆转这些作用。因此，HDAC6 抑制剂在这些细胞中也可降低 ERK 活性。我们的研究结果将 HDAC6 介导的 MT 调节与致癌性 Shp2 和 ERK 调节联系起来，表明 HDAC6 抑制剂在涉及 Shp2 失活的疾病中具有治疗潜力。
