Emerging role of <scp>ARHGAP29</scp> in melanoma cell phenotype switching

Rho GTPase-activating protein 29 (ARHGAP29) is an inhibitor of the Ras homolog family member A (RhoA)/Rho-associated protein kinase (ROCK) signaling pathway. Studies in non-melanoma cancer entities described that ARHGAP29 modulates the actin cytoskeleton, promoting tumor cell invasion. In melanoma, its function has been completely unknown. Our transcriptomic analyses revealed a strong expression of ARHGAP29 in melanoma cell lines compared to melanocytes. Therefore, we hypothesized that ARHGAP29 affects the migratory potential of melanoma cells and drives melanoma progression. By knocking down ARHGAP29, we demonstrated that it promotes a spread cell morphology through regulating the RhoA/ROCK pathway. Further investigations indicated the role of ARHGAP29 on SMAD activity. Interestingly, our data showed that ARHGAP29 expression is promoting tumor cell plasticity through a mesenchymal-like, invasive phenotype. To summarize, this study gives insights into the functional role of ARHGAP29 and its downstream signaling in melanoma. Our findings provided evidence supporting the hypothesis that ARHGAP29 is an important player in melanoma progression, a promising and novel target in melanoma treatment.