Blockade of neddylation facilitates cancer cell migration by stabilizing c-Src

Abstract

c-Src, a well-known proto-oncogene, mediates tumor progression properties including proliferation, angiogenesis, adhesion, and migration. It is well-characterized that the stability of active c-Src is regulated by ubiquitination while other post-translational modifications of c-Src have been unknown. Here, I found that the stability of c-Src is regulated by neddylation. Furthermore, c-Cbl turned out as an E3 ligase for conjugation of NEDD8 to c-Src. Moreover, the inhibition of c-Src neddylation markedly blocked its ubiquitination. To my surprise, the blockade of neddylation by NAE inhibitor MLN4924 or si-NEDD8 promoted cancer cell migration through the elevated stability of c-Src. Such consequences by inhibition of neddylation were abolished either by the treatment of Src-family kinase inhibitor PP2 or c-Src-targeting siRNA. Also the blockade of neddylation activated PI3K/Akt/mTOR pathway in a c-Src-dependent manner. Inhibitors of PI3K/Akt/mTOR pathway also could abolish cancer cell migration induced by MLN4924. Taken together, c-Src was identified as a novel substrate for neddylation that facilitates ubiquitination-dependent degradation, which blocks the migration of cancer cells via PI3K/Akt/mTOR pathway. My study provided a new insight about the effect of c-Src modification in tumor progression.