VAV2 Drives EGFR-Mediated Rac1 Responses in Prostate Cancer

Abstract

The small G-protein Rac1 is a central player in cancer progression and metastatic dissemination. Rac1 has been established as a bona fide effector of receptor tyrosine kinases, acting as a signaling node for motility, invasiveness, mitogenesis, and gene expression. Previous studies demonstrated that Rac1 is hyperactivated in aggressive cellular models of prostate cancer. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of Rac1 results in impaired proliferation and migration of prostate cancer cells. Rac1-null cells display profound alterations in transcriptional programs, particularly those associated with cell adhesion and extracellular matrix regulation. Combined expression profiling and unbiased RNAi screening of Rac1 guanine nucleotide exchange factors identified VAV2 as the foremost mediator EGF-induced GTP loading onto Rac1 in prostate cancer cells. Depletion of VAV2 from prostate cancer cells significantly reduced their proliferative and migratory capacities without affecting the expression of Rac1-regulated genes, suggesting that VAV2 controls a discrete subset of Rac1-dependent cellular responses. IHC assessment in human prostate biopsies showed significant VAV2 overexpression in tumor areas. Bioinformatic analysis revealed a strong correlation between VAV2 expression and poor clinical prognosis. In addition to uncovering a prominent role for VAV2–Rac1 as an effector pathway mediating EGFR-driven proliferative and migratory responses in prostate cancer cells, our findings underscore the potential prognostic value of VAV2 in human prostate cancer progression.