Scaffolding protein IQGAP1 is dispensable, but its overexpression promotes hepatocellular carcinoma via YAP1 signaling

Evan R. Delgado, Hanna L. Erickson, Junyan Tao, Satdarshan P. Monga, Andrew W. Duncan, Sayeepriyadarshini Anakkb

Research output: Contribution to journalArticlepeer-review

Abstract

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 protumorigenic processes, such as cell proliferation, motility, and adhesion. IQGAP1 can integrate multiple signaling pathways and could be an effective antitumor target. Therefore, we examined the role of 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, we report that the tumor burden and cell proliferation in the diethylnitrosamine-induced liver carcinogenesis model in Iqgap12/2 mice may be 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) b-catenin and MET. Here, increasing IQGAP1 expression in vivo does not alter b-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.

Original languageEnglish (US)
Article numbere00596
JournalMolecular and cellular biology
Volume41
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • IQGAP1
  • Liver cancer
  • MET
  • Scaffold protein
  • YAP

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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