Abstract
Recent studies have revealed that ARHGEF7 is upregulated in many malignant tumors, but the underlying molecular mechanisms to this response remain to be fully elucidated. In this study, we confirm that ARHGEF7 physically interacts with KLHL2, which was previously identified to be an E3 ubiquitin ligase. KLHL2 is capable of promoting ARHGEF7 degradation via the ubiquitin-proteasome pathway. We identify that the Kelch domain of KLHL2 is necessary for binding with ARHGEF7 and downstream activities. In addition, we find that ARHGEF7 is overexpressed in clear cell renal cell carcinoma (ccRCC) specimens, and that the level of expression negatively correlates with that of KLHL2. Moreover, we utilize knockdown loss-of-function assays to demonstrate that ARHGEF7 in 786-O and A498 cell lines can act as a regulator of cell proliferation, migration and invasion, and that these effects can be reversed by KLHL2 inactivation. Taken together, our data suggest that ARHGEF7 is a putative oncogene that functions via an interaction with KLHL2, and control of ARHGEF7 can be a potential future target to inhibit tumor progression.