The epithelial-mesenchymal transition (EMT) is the process by which epithelial cells lose their tightly packed polarized characteristics and acquire a migratory mesenchymal phenotype. EMT plays a pivotal role in embryonic development, wound healing, tissue regeneration, organ fibrosis and cancer progression. The basic helix-loop-helix (bHLH) transcription factors TWIST1/2 are key EMT-inducing transcription factors that govern transcription of EMT-associated genes. Although regulation of TWIST1 activity and stability has been well studied, little is known about how TWIST2 is post-translationally regulated. Here we have identified ZNF451, a SUMO2/3 specific E3 ligase, as a novel regulator of TWIST2 in promoting its stability. ZNF451 directly binds to and SUMOylates TWIST2 at K129 residue, and consequently blocks ubiquitination and proteasome-dependent degradation of TWIST2. Ectopic expression of ZNF451 increases the protein level of TWIST2 in mammary epithelial cells, leading to increased expression of mesenchymal markers, whereas depletion of ZNF451 suppresses mesenchymal phenotypes. Collectively, our findings demonstrate that ZNF451 plays a vital role in EMT through SUMOylation-dependent stabilization of TWIST2.