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Abstract
Growing evidence indicates that the epithelial to mesenchymal (E/M) hybrid state plays a key role in tumorigenesis. Importantly, a hybrid mesenchymal to epithelial transition (MET) state in which individual cells express both epithelial and mesenchymal markers was recently identified in vivo, further strengthening the bonds between the hybrid EMT state and cancer progression. However, the role and the molecular mechanisms by which the hybrid MET state is maintained in triple-negative breast cancer cells (TNBC) remain elusive. Here, we find that loss of ZHX2 expression results in the hybrid MET phenotype in mesenchymal TNBC cells. Mechanistically, through directly binding to the CDH1 promoter, depletion of ZHX2 specifically reactivates expression of CDH1 encoding E-cadherin, an epithelial marker that is crucial for maintaining epithelial phenotype. Functionally, loss of ZHX2 expression enriches the hybrid MET cells and inhibits the migration and dissemination of TNBC cells or organoids, which could be reversed by restoration of E-cadherin. Moreover, depletion of ZHX2 suppresses lung metastasis in preclinical models of TNBC. In patients with TNBC, ZHX2 expression was amplified and negatively correlated with the expression of E-cadherin. These findings suggest that loss of ZHX2 promotes the hybrid MET state to impair TNBC progression.
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1 Huazhong University of Science and Technology, National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Wuhan, China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223)
2 Fujian Medical University, Stem Cell Laboratory, the Second Affiliated Hospital, Quanzhou, China (GRID:grid.256112.3) (ISNI:0000 0004 1797 9307)
3 Huazhong University of Science and Technology, Cancer Center, Union Hospital, Tongji Medical College, Wuhan, China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223); Huazhong University of Science and Technology, Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Wuhan, China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223)