The oncogenic E3 ligase TRIP12 suppresses epithelial-mesenchymal transition (EMT) and metastasis-related processes through ZEB1/2

Abstract

Thyroid hormone receptor interactor 12 (TRIP12) is an E3 ligase most notably involved in the proteolytic degradation of the tumor suppressor p14ARF. Through this process, it is proposed that TRIP12 plays an oncogenic role in tumor initiation and growth. However, its role in other cancer processes such as metastasis is unknown. In this study, using publicly available cancer patient datasets, we found TRIP12 to be associated with distant metastasis-free survival in breast cancer, suggesting a contrary cancer process inhibitory role in metastasis. Following TRIP12 depletion in the MCF10A breast epithelial cell model, an epithelial-mesenchymal transition (EMT) shift occurred with concomitant changes in EMT cell adhesion markers identified through RNA-seq. In line with EMT changes, TRIP12-depleted cells lose polarity and dislodge from bulk cells at a higher frequency. Furthermore, ectopic TRIP12 expression sensitized cells to anoikis, a major barrier against metastasis. Mechanistically, TRIP12 suppresses EMT through inhibiting ZEB1/2 gene expression and ZEB1/2 depletion rescues EMT markers and cellular behavior. Overall, our study delineates TRIP12s role in inhibition of EMT and metastasis-related processes, and implies a suppression role in breast cancer metastasis.