Deubiquitinating enzyme OTUD4 regulates metastasis in triple-negative breast cancer by stabilizing Snail1

Metastasis is the primary cause of cancer-related deaths and remains poorly understood. Deubiquitinase OTU domain containing 4 (OTUD4) has been reported to regulate antiviral immune responses and resistance to radio- or chemo-therapies in certain cancers. However, the role of OTUD4 in cancer metastasis remain unknown. Here, we demonstrate that the depletion of OTUD4 in triple-negative breast cancer (TNBC) cells markedly suppress cell clonogenic ability, migration, invasion and cancer stem cell population in vitro as well as metastasis in vivo. Mechanistically, the tumor promoting function of OTUD4 is mainly mediated by deuiquitinating and stabilizing Snail1, one key transcriptional factor in the epithelial-mesenchymal transition. The inhibitory effect of targeting OTUD4 could be largely reversed by the reconstitution of Snail1 in OTUD4-deficient cells. Overall, our study establishes the OTUD4-Snail1 axis as an important regulatory mechanism of breast cancer metastasis and provides a rationale for potential therapeutic interventions in the treatment of TNBC.