Yi-Zih Kuo1, Ya-Rong Kang2, Wei-Lun Chang3, Lydia Chin-Ling Sim2, Tzu-Chin Hsieh2, Chu-Han Chang2, Yi-Ching Wang4, Ching-Jung Tsai2, Li-Chun Huang2, Sen-Tien Tsai5, Li-Wha Wu6,7. 1. Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan, Republic of China. 2. Institutes of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan, Republic of China. 3. Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, 70428, Taiwan, Republic of China. 4. Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan, Republic of China. 5. Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan, Republic of China. T602511@mail.ncku.edu.tw. 6. Institutes of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan, Republic of China. liwhawu@mail.ncku.edu.tw. 7. Department of Laboratory Science and Technology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China. liwhawu@mail.ncku.edu.tw.
Abstract
PURPOSE: Although YAP1 and TAZ are believed to be equivalent downstream effectors of the Hippo pathway, differential expression of YAP1 or TAZ suggests distinct functions during cancer progression. The exact role of YAP1 and TAZ in esophageal cancer, the 6th leading cancer-related mortality in the world, remains elusive. METHODS: Following single or double manipulation of YAP1 or TAZ expression, we subjected these manipulated cells to proliferation, migration, invasion, and xenograft tumorigenesis assays. We used RT-qPCR and Western blotting to examine their expression in the manipulated cells with or without inhibition of transcription or translation. We also examined the impact of YAP1 or TAZ deregulation on clinical outcome of esophageal cancer patients from the TCGA database. RESULTS: We found that YAP1 functions as a tumor suppressor whereas TAZ exerts pro-tumor functions in esophageal cancer cells. We also found a significant increase in TAZ mRNA expression upon YAP1 depletion, but not vice versa, despite the downregulation of CTGF and CYR61, shared targets of YAP1 and TAZ, in xenografted tissue cells. In addition to transcriptional regulation, YAP1-mediated TAZ expression was found to occur via protein synthesis. Restored TAZ expression mitigated YAP1-mediated suppression of cellular behavior. By contrast, TAZ silencing reduced the promoting effect exerted by YAP1 depletion on cellular behaviors. The observed anti-tumor function of YAP1 was further supported by a better overall survival among esophageal cancer patients with a high YAP1 expression. CONCLUSION: From our data we conclude that YAP1 functions as a suppressor and negatively regulates pro-tumor TAZ expression via transcriptional and translational control in esophageal cancer.
PURPOSE: Although YAP1 and TAZ are believed to be equivalent downstream effectors of the Hippo pathway, differential expression of YAP1 or TAZ suggests distinct functions during cancer progression. The exact role of YAP1 and TAZ in esophageal cancer, the 6th leading cancer-related mortality in the world, remains elusive. METHODS: Following single or double manipulation of YAP1 or TAZ expression, we subjected these manipulated cells to proliferation, migration, invasion, and xenograft tumorigenesis assays. We used RT-qPCR and Western blotting to examine their expression in the manipulated cells with or without inhibition of transcription or translation. We also examined the impact of YAP1 or TAZ deregulation on clinical outcome of esophageal cancer patients from the TCGA database. RESULTS: We found that YAP1 functions as a tumor suppressor whereas TAZ exerts pro-tumor functions in esophageal cancer cells. We also found a significant increase in TAZ mRNA expression upon YAP1 depletion, but not vice versa, despite the downregulation of CTGF and CYR61, shared targets of YAP1 and TAZ, in xenografted tissue cells. In addition to transcriptional regulation, YAP1-mediated TAZ expression was found to occur via protein synthesis. Restored TAZ expression mitigated YAP1-mediated suppression of cellular behavior. By contrast, TAZ silencing reduced the promoting effect exerted by YAP1 depletion on cellular behaviors. The observed anti-tumor function of YAP1 was further supported by a better overall survival among esophageal cancer patients with a high YAP1 expression. CONCLUSION: From our data we conclude that YAP1 functions as a suppressor and negatively regulates pro-tumor TAZ expression via transcriptional and translational control in esophageal cancer.
Authors: R Ehsanian; M Brown; H Lu; X P Yang; A Pattatheyil; B Yan; P Duggal; R Chuang; J Doondeea; S Feller; M Sudol; Z Chen; C Van Waes Journal: Oncogene Date: 2010-08-23 Impact factor: 9.867