The E3 Ligase NEDD4L Prevents Colorectal Cancer Liver Metastasis via Degradation of PRMT5 to Inhibit the AKT/mTOR Signaling Pathway

Abstract Colorectal cancer is the second most common cause of cancer mortality worldwide, and liver metastasis is the major cause of death of patients with colorectal cancer. Dysfunctional E3 ligase activity has recently been shown to be associated with colorectal cancer. However, the key E3 ligases affecting colorectal cancer liver metastasis remain unknown. Therefore, an shRNA library targeting 156 E3 ubiquitin ligases has been used to perform an in vivo loss‐of‐function screen of a human colorectal cancer cell line in a mouse model of liver metastasis. The screen reveals that neural precursor cell expressed developmentally down‐regulated gene 4‐like (NEDD4L) knockdown promotes colorectal cancer liver metastasis. Mechanistic studies reveal that NEDD4L binds to the PPNAY motif in protein arginine methyltransferase 5 (PRMT5) and ubiquitinates PRMT5 to promote its degradation. PRMT5 degradation attenuates the arginine methylation of AKT1 to inhibit the AKT/mTOR signaling pathway. The effect of NEDD4L decreases colorectal cancer cell proliferation to suppress colonization. This study is the first to show that PRMT5 is a substrate of NEDD4L and reveals not only the metastasis‐inhibiting function of NEDD4L but also a novel mechanism by which NEDD4L prevents colorectal cancer liver metastasis. These findings may provide a new preventive strategy for liver metastasis.