IGF2BP3 Promotes Autophagy-Mediated TNBC Metastasis via M6A-Dependent, Cap-Independent c-Met Translation

Tumor metastasis involves a series of complex processes and is a major challenge in clinical treatment. The cooperation of epigenetic modifications and metabolic adaptations endows tumor cells with dynamic adaptations for survival in variable environments, which is crucial for tumor metastasis and worth exploring in depth. In this study, we found IGF2BP3 could link epigenetic modification and metabolic adaptation in promoting autophagy-mediated triple-negative breast cancer (TNBC) metastasis. As a TNBC specifically high expressed N6-methyladenosine (m6A) binding protein, IGF2BP3 could bind to the m6A motif of c-Met mRNA, regulating autophagy-mediated epithelial-to-mesenchymal transition (EMT) progress by c-Met/PI3K/AKT/mTOR pathway. Moreover, through the recruitment of eIF4G2 as a collaborator, IGF2BP3 induced the changes in c-Met protein expression not by affecting mRNA stability, but by facilitating its mRNA translation initiation in an m6A-dependent and cap-independent manner. In conclusion, our study extended the role of IGF2BP3 in autophagy mediated TNBC metastasis, found IGF2BP3 could bind to the m6A motif on the 5', 3'-UTR of c-Met mRNA to facilitate its translation in a cap-independent manner.