ARHGAP4 regulates the cell migration and invasion of pancreatic cancer by the HDAC2/β-catenin signaling pathway
ARHGAP4 regulates the cell migration and invasion of pancreatic cancer by the HDAC2/β-catenin signaling pathway
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DOI：
10.1093/carcin/bgz067
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发表时间：
2019-11-01
期刊：
影响因子：
4.7
通讯作者：
Meng, Zhiqiang
中科院分区：
文献类型：
--
作者：
Shen, Yehua;Xu, Litao;Meng, Zhiqiang
β-连环蛋白是钙粘蛋白复合体的一个亚单位，在Wnt信号通路中扮演细胞内信号转导的角色，介导多种细胞过程，如细胞迁移和侵袭。HDAC2(组蛋白脱乙酰酶2)，一种脱乙酰酶，在Wnt靶向基因的启动子区域保持组蛋白H3处于去乙酰化状态，负向调节β-连环素的激活。然而，HDAC2/β-连环蛋白途径的调控仍不清楚。在此，我们报道了ARHGAP4作为一种新的β-连环蛋白途径的调节因子，在体外调节胰腺癌的细胞侵袭和迁移以及下游效应分子MMP2和MMP9的表达。在机制上，ARHGAP4与HDAC2相互作用并泛化HDAC2，HDAC2反过来抑制β-连环蛋白的激活。此外，HDAC2抑制剂CAY10683和Wnt/β-catenin途径抑制剂XAV939的处理可减弱ARHGAP4沉默对胰腺癌细胞的影响。总体而言，我们的发现证实了ARHGAP4是HDAC2/β-连环蛋白途径的一个新的调节因子，在肿瘤发生中起着关键作用。
beta-catenin is a subunit of the cadherin protein complex and acts as an intracellular signal transducer in the Wnt signaling pathway that mediates multiple cellular processes, such as cell migration and invasion. HDAC2 (histone deacetylase 2), a deacetylase that maintains histone H3 in a deacetylated state in the promoter region of Wnt-targeted genes where beta-catenin is bound, negatively regulating beta-catenin activation. However, the regulation of HDAC2/beta-catenin pathway remains unclear. Here, we report ARHGAP4 as a new regulator of the beta-catenin pathway that regulates cell invasion and migration of pancreatic cancer as well as the downstream effector MMP2 and MMP9 expression in vitro. Mechanistically, ARHGAP4 interacts with and ubiquitinates HDAC2, which in turn inhibits beta-catenin activation. Furthermore, treatment of CAY10683, an HDAC2 inhibitor, and XAV939, a Wnt/beta-catenin pathway inhibitor, attenuated the effects of ARHGAP4 silencing on pancreatic cancer cells. Overall, our findings establish ARHGAP4 as a novel regulator of HDAC2/beta-catenin pathway with a critical role in tumorigenesis.