Role of IQGAP1 in Carcinogenesis

Abstract

Scaffolding proteins can play important roles in cell signaling transduction. IQ motif-containing GTPase-activating protein 1 (IQGAP1) influences many cellular activities by scaffolding multiple key signaling pathways, including ones involved in carcinogenesis. Two decades of studies provide evidence that IQGAP1 plays an essential role in promoting cancer development. IQGAP1 is overexpressed in many types of cancer, and its overexpression in cancer is associated with lower survival of the cancer patient. Here, we provide a comprehensive review of the literature regarding the oncogenic roles of IQGAP1. We start by describing the major cancer-related signaling pathways scaffolded by IQGAP1 and their associated cellular activities. We then describe clinical and molecular evidence for the contribution of IQGAP1 in different types of cancers. In the end, we review recent evidence implicating IQGAP1 in tumor-related immune responses. Given the critical role of IQGAP1 in carcinoma development, anti-tumor therapies targeting IQGAP1 or its associated signaling pathways could be beneficial for patients with many types of cancer.

Keywords: HPV; PI3K; Ras; Wnt; cancer; scaffold.

Figure 1

Summary of TCGA RNAseq data showing high levels of IQGAP1 is associated with poorer prognosis in cancers of pancreas, urethra, and melanoma. TCGA RNA-seq data were accessed through the Human Protein Atlas website (https://www.proteinatlas.org/ENSG00000140575-IQGAP1/pathology (accessed on 03 Aug 2021)). Cutoff for IQGAP1 levels was suggested by the database as shown on the website and is based upon on survival analysis that yields the maximal difference in survival between the two groups at the lowest log-rank p-value. Kaplan–Meier survival analysis was performed on all datasets provided by the website using GraphPad Prism 8.3.1 (GraphPad Software, San Diego, CA, United States). The types of cancer we analyzed included cancers of the thyroid, lung, colon, head and neck, stomach, liver, pancreas, kidney, urethra, prostate, testis, breast, cervix, endometrium, ovary, glioma, and melanoma. Due to data availability, we focused only on survival data over the first 3 years for glioma and melanoma patients. For all other cancers, we looked at patient survival over 5 years. Of the cancers analyzed, a high level of IQGAP1 mRNA expression was significantly associated with poorer prognosis only in head and neck cancer [51], pancreatic cancer (graph (A)), urothelial cancer (graph (B)), and melanoma (graph (C)).

Figure 2

Roles of IQGAP1 in cancer development. (1) IQGAP1 regulatory factors: IQGAP1′s activity can be regulated by different cancer development factors, including the genetic changes to the IQGAP1 gene, post-translational modifications on the IQGAP1 protein, activations of signaling receptors, miRNA, or other non-receptor regulatory proteins. Example candidates in each category are summarized in the gray rectangles. (2) The IQGAP1 protein: a schematic diagram of human IQGAP1 protein, with each of the five main binding domains highlighted in blue and the numbers above indicating amino acid positions for each domain. (3) Cancer-related pathways and cancer hallmarks: list of IQGAP1-mediated pathways and related cancer hallmark events. The pathways and the pathway-regulated hallmarks are color-coded. Dash line indicates a connection between IQGAP1 and this cancer hallmark, but no mechanism is proposed. (4) Types of cancer with IQGAP1-mediated cancer hallmarks: BC, breast cancer; CRC, colorectal cancer; ESCC, esophageal squamous cell carcinoma; GC, gastric cancer; HepC, hepatic cancer/liver cancer; HNSCC, head and neck squamous cell carcinoma; LC, lung cancer; OC, ovarian cancer; PanC, pancreatic cancer. Black font indicates that IQGAP1 has been reported to regulate this hallmark through at least one proposed mechanism in this type of cancer; red font indicates that IQGAP1 has been reported to regulate this hallmark in this cancer, but no clear mechanism has been proposed.