Author: Evan R Delgado, Hanna L Erickson, Junyan Tao, Satdarshan P Monga, Andrew W Duncan, Sayeepriyadarshini Anakk
Title: Scaffolding Protein IQGAP1 is Dispensable But Its Overexpression Promotes Hepatocellular Carcinoma via YAP1 Signaling
Summary: IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffolding protein that is overexpressed in a number of cancers, including liver cancer, and is associated with pro-tumorigenic processes such as cell proliferation, motility, and adhesion. IQGAP1 can integrate multiple signaling pathways and could be an effective anti-tumor target. Therefore, we examined the role for IQGAP1 in tumor initiation and promotion during liver carcinogenesis. We found that ectopic overexpression of IQGAP1 in the liver is not sufficient to initiate tumorigenesis. Moreover, the tumor burden and cell proliferation in the DEN-induced liver carcinogenesis model in Iqgap1-/- mice maybe driven by MET signaling. In contrast, IQGAP1 overexpression enhanced YAP activation and subsequent NUAK2 expression to accelerate and promote hepatocellular carcinoma (HCC) in a clinically relevant model expressing activated (S45Y) β-catenin and MET. Here, increasing IQGAP1 expression in vivo does not alter β-catenin or MET activation; instead, it promotes YAP activity. Overall, we demonstrate that although IQGAP1 expression is not required for HCC development, the gain of IQGAP1 function promotes the rapid onset and increased liver carcinogenesis. Our results show that an adequate amount of IQGAP1 scaffold is necessary to maintain the quiescent status of the liver.
Source: Molecular and Cellular Biology. 2021 Feb 1;MCB.00596-20. Online ahead of print.