Altogether, our work uncovers the first known non-histone protein methylation signaling mechanism that regulates directly cell motility and invasion, deciphers the pro-metastatic role and mechanisms of action of SMYD2 methyltransferase in breast cancer and validates SMYD2 as a clinically actionable target to prevent metastases, the leading cause of breast cancer mortality. Here, SMYD2 is linked to breast cancer.