| Autor: |
Lee KK; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. A0123884@u.nus.edu., Rajagopalan D; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Bhatia SS; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Tirado-Magallanes R; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Chng WJ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore.; Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, Singapore., Jha S; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. csisjha@nus.edu.sg.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. csisjha@nus.edu.sg. |
| Abstrakt: |
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 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 an inhibitory role in metastasis. Following TRIP12 depletion, 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 gained mesenchymal traits such as loss of cell polarity, dislodgement from bulk cells at a higher frequency, and increased cellular motility. Furthermore, ectopic TRIP12 expression sensitized cells to anoikis. Mechanistically, TRIP12 suppresses EMT through inhibiting ZEB1/2 gene expression, and ZEB1/2 depletion rescues EMT markers and mesenchymal behavior. Overall, our study delineates TRIP12's role in inhibition of EMT and implies a potential suppressive role in breast cancer metastasis. |
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