Aquaporin 9 is involved in CRC metastasis through DVL2-dependent Wnt/βcatenin signaling activation

Abstract

Background: Aquaporin 9 (AQP9), an aquaporin protein family member, is permeable to water and other small molecules. Aquaporins play important role in a variety of pathophysiological processes, fostering growing interests in identifying them as diagnostic and therapeutic targets in cancer. We previously found that AQP9 is related to the efficacy of chemotherapy in CRC patients, but its role and regulating mechanism in CRC progression remains unclear. Results: In this study, we find that AQP9 is highly expressed in metastatic CRC. AQP9 overexpression induces reduced cell roundness and enhanced cell motility in CRC, which contribute to cancer metastasis. We further show that AQP9 interacts with DVL2 via the C-terminal SVIM motif, resulting in DVL2 stabilization and nuclear β-catenin increase. Deletion of the SVIM motif disrupts the AQP9-DVL2 interaction and results in the repression of TCF/LEF transcriptional activity, supporting the involvement of DVL2 in AQP9 induced Wnt/β-catenin pathway activation. Additionally, we identify the E3 ligase NEDD4L as an modulator in regulating the ubiquitination and degradation of AQP9. Conclusions: Collectively, our study reveals the important role of AQP9 in regulating DVL2 stabilization and Wnt/β-catenin signaling to promote CRC metastasis. Targeting NEDD4L-AQP9-DVL2 axis might be with therapeutic usefulness in metastatic CRC treatment.