Zinc-Dependent Regulation of ZEB1 and YAP1 Coactivation Promotes Epithelial-Mesenchymal Transition Plasticity and Metastasis in Pancreatic Cancer. - 2021
[en] [en] BACKGROUND: Pancreatic cancer is characterized by extensive metastasis. Epithelial-mesenchymal transition (EMT) plasticity plays a critical role in tumor progression and metastasis by maintaining the transition between EMT and mesenchymal-epithelial transition states. Our aim is to understand the molecular events regulating metastasis and EMT plasticity in pancreatic cancer.
METHODS: The interactions between a cancer-promoting zinc transporter ZIP4, a zinc-dependent EMT transcriptional factor ZEB1, a coactivator YAP1, and integrin α3 (ITGA3) were examined in human pancreatic cancer cells, clinical specimens, spontaneous mouse models (KPC and KPCZ) and orthotopic xenografts, and 3-dimensional spheroid and organoid models. Correlations between ZIP4, miR-373, and its downstream targets were assessed by RNA in situ hybridization and immunohistochemical staining. The transcriptional regulation of ZEB1, YAP1, and ITGA3 by ZIP4 was determined by chromatin immunoprecipitation, co-immunoprecipitation, and luciferase reporter assays.
RESULTS: The Hippo pathway effector YAP1 is a potent transcriptional coactivator and forms a complex with ZEB1 to activate ITGA3 transcription through the YAP1/transcriptional enhanced associate domain (TEAD) binding sites in human pancreatic cancer cells and KPC-derived mouse cells. ZIP4 upregulated YAP1 expression via activation of miR-373 and inhibition of the YAP1 repressor large tumor suppressor 2 kinase (LATS2). Furthermore, upregulation of ZIP4 promoted EMT plasticity, cell adhesion, spheroid formation, and organogenesis both in human pancreatic cancer cells, 3-dimensional spheroid model, xenograft model, and spontaneous mouse models (KPC and KPCZ) through ZEB1/YAP1-ITGA3 signaling axis.
CONCLUSION: We demonstrated that ZIP4 activates ZEB1 and YAP1 through distinct mechanisms. The ZIP4-miR-373-LATS2-ZEB1/YAP1-ITGA3 signaling axis has a significant impact on pancreatic cancer metastasis and EMT plasticity.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Liu, Mingyang; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Zhang, Yuqing; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Yang, Jingxuan; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Zhan, Hanxiang; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
Zhou, Zhijun; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Jiang, Yuanyuan; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China
Shi, Xiuhui ; Université de Liège - ULiège > Département de pharmacie ; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Fan, Xiao; Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Zhang, Junxia; Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Luo, Wenyi; Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Fung, Kar-Ming A; Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Xu, Chao; Department of Biostatistics and Epidemiology, Hudson College of Public Health, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Bronze, Michael S; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Houchen, Courtney W; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Li, Min ; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address: Min-Li@ouhsc.edu
NCI - National Cancer Institute William and Ella Owens Medical Research Foundation NIH - National Institutes of Health
Funding text :
Funding This work was supported in part by National Institutes of Health (NIH) grants R01 CA186338-01A1, R01 CA203108, and R01 CA247234-01; the William and Ella Owens Medical Research Foundation (Min Li), and NIH/National Cancer Institute award P30CA225520.
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