ARHGAP4 regulates the cell migration and invasion of pancreatic cancer by the HDAC2/β-catenin signaling pathway.

Abstract

β-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 β-catenin is bound, negatively regulating β-catenin activation. However, the regulation of HDAC2/β-catenin pathway remains unclear. Here, we report ARHGAP4 as a new regulator of the β-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 β-catenin activation. Furthermore, treatment of CAY10683, an HDAC2 inhibitor, and XAV939, a Wnt/β-catenin pathway inhibitor, attenuated the effects of ARHGAP4 silencing on pancreatic cancer cells. Overall, our findings establish ARHGAP4 as a novel regulator of HDAC2/β-catenin pathway with a critical role in tumorigenesis.

• Authors: Yehua Shen, Litao Xu, Zhouyu Ning, Luming Liu, Junhua Lin, Hao Chen, Zhiqiang Meng
• Journal: Carcinogenesis (Carcinogenesis) Vol. 40 Issue 11 Pg. 1405-1414 (Nov 25 2019) ISSN: 1460-2180 [Electronic] England
• PMID: 30958531 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• ARHGAP4 protein, human
• GTPase-Activating Proteins
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• HDAC2 protein, human
• Histone Deacetylase 2

Topics

• Adult
• Aged
• Aged, 80 and over
• Cell Line, Tumor
• Cell Movement
• Female
• GTPase-Activating Proteins (metabolism)
• Gene Expression Regulation, Neoplastic
• Histone Deacetylase 2 (metabolism)
• Humans
• Male
• Matrix Metalloproteinase 2 (genetics)
• Matrix Metalloproteinase 9 (genetics)
• Middle Aged
• Neoplasm Invasiveness
• Pancreatic Neoplasms (genetics, metabolism, physiopathology)
• Wnt Signaling Pathway