FYN is required for ARHGEF16 to promote proliferation and migration in colon cancer cells

Bei Yu,Yao Wang,Limin Chen,Linlin Xu,Zhenyu Zhai,Shiwen Luo,Yehong Yan,Yiting Wang,Hongying Jiang

doi:10.1038/s41419-020-02830-1

Abstract

ARHGEF16 is a recently identified Rho-family guanine nucleotide exchange factor (GEF) that has been implicated in the activation of Rho-family GTPases such as Rho G, Rac, and Cdc42. However, its functions in colon cancer cell proliferation and migration are not well understood. In this study, we showed that ARHGEF16 was highly expressed in clinical specimens of colon cancer. In colon cancer cells, ARHGEF16-stimulated proliferation and migration in vitro and in vivo. Furthermore, we identified a nonreceptor tyrosine kinase, FYN, as a novel partner of ARHGEF16. Knocking down FYN expression decreased ARHGEF16 protein level in colon cancer cells. We further demonstrated that ARHGEF16-induced colon cancer cell proliferation and migration were dependent on FYN since knockdown FYN abolished the ARHGEF16-induced proliferation and migration of colon cancer cells. The FYN-ARHGEF16 axis mediates colon cancer progression and is a potential therapeutic target for colon cancer treatment.

Highlights

Introduction The small GTPases of theRho family (Rho-familyGTPases) have manifold physiological functions, such as roles in cell adhesion, cytoskeleton regulation, cell proliferation and motility, and tumorigenesis[1,2,3]
Previous reports from our laboratory have shown that aberrant activation of Gli[2], a glioma-associated oncogene and zinc-finger transcription factor for hedgehog signaling, increases the transcript level of ARHGEF16, while ARHGEF16 interacts with cytoskeleton-associated protein 5 (CKAP5) to promote the proliferation and migration of glioma cells[13]
ARHGEF16 is highly expressed in colon cancer tissues To investigate the role of ARHGEF16 in colon cancer, we evaluated ARHGEF16 levels in seven paired samples of colon cancer tissue and adjacent normal tissue by WB analysis and revealed that the expression of the ARHGEF16 protein was higher in the colon cancer tissue samples than in the normal tissue samples (Fig. 1a)

Summary

Introduction

GTPases) have manifold physiological functions, such as roles in cell adhesion, cytoskeleton regulation, cell proliferation and motility, and tumorigenesis[1,2,3]. GEFs play important signal transduction roles in physiological and oncopathological events by regulating the activity of Rho GTPases. Previous reports from our laboratory have shown that aberrant activation of Gli[2], a glioma-associated oncogene and zinc-finger transcription factor for hedgehog signaling, increases the transcript level of ARHGEF16, while ARHGEF16 interacts with cytoskeleton-associated protein 5 (CKAP5) to promote the proliferation and migration of glioma cells[13]. ARHGEF16 is critical for cancer cell proliferation and growth as well as tumorigenesis It remains unclear whether there are other yet unknown ARHGEF16 signaling pathways that are important in the progression of colon cancer

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Conclusion