ATAD2 interacts with C/EBPβ to promote esophageal squamous cell carcinoma metastasis via TGF-β1/Smad3 signaling
| Autor: | Wen-Qiong Xue, Xiao-Hui Zheng, Xi-Zhao Li, Yijun Zhang, Jiang-Bo Zhang, Xia-Ting Tong, Zi-Yi Wu, Lian-Jing Cao, Dong Chen, Wei Hua Jia, Si-Qi Dong |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Esophageal Neoplasms Mice Nude lcsh:RC254-282 Metastasis Transforming Growth Factor beta1 Mice 03 medical and health sciences 0302 clinical medicine In vivo Esophageal squamous cell carcinoma medicine Animals Humans Gene silencing Smad3 Protein ATAD2 Neoplasm Metastasis TGF-β signaling pathway Cell Proliferation Mice Inbred BALB C Chemistry Research CCAAT-Enhancer-Binding Protein-beta Cell migration Middle Aged medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens DNA-Binding Proteins 030104 developmental biology Oncology Apoptosis Lymphatic Metastasis 030220 oncology & carcinogenesis C/EBPβ Cancer research ATPases Associated with Diverse Cellular Activities Heterografts Female Signal transduction Chromatin immunoprecipitation Signal Transduction Transforming growth factor |
| Zdroj: | Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-16 (2021) Journal of Experimental & Clinical Cancer Research : CR |
| ISSN: | 1756-9966 |
| Popis: | Background Distant metastasis is the leading cause of death for esophageal squamous cell carcinoma (ESCC) with limited treatment options and unsatisfactory effectiveness. Bromodomain (BRD) containing proteins are emerging targets for cancer therapy with promising effects. As a unique member of BRD family, the function and molecular mechanism of ATAD2 in cancer development is seldomly investigated. Methods The clinical impact of ATAD2 was assessed both at RNA and protein level in 75 and 112 ESCC patients separately. The biological function of ATAD2 was investigated in vitro and in vivo. Signaling pathway and downstream effectors of ATAD2 were identified by RNA sequencing, luciferase reporter, co-immunoprecipitation, chromatin immunoprecipitation, immunofluorescence and western blot assay. Results We found that elevated ATAD2 expression was significantly associated with lymph node metastasis, advanced clinical stage as well as poor survival of ESCC patients. Silencing ATAD2 significantly suppressed ESCC cell migration and invasion in vitro, and inhibited tumor growth and lung metastasis in vivo. Mechanically, we identified a new cofactor, C/EBPβ. ATAD2 directly interacted with C/EBPβ and promoted its nuclear translocation, which directly bound to the promoter region of TGF-β1 and activated its expression. Further, we demonstrated that TGF-β1 activated its downstream effectors in a Smad3 dependent manner. In addition, we further found that ATAD2 promoted ESCC metastasis through TGF-β signaling induced Snail expression and the subsequent epithelial-mesenchymal transition. Conclusion Our findings demonstrated the pro-metastatic function of ATAD2 and uncovered the new molecular mechanism by regulating C/EBPβ/TGF-β1/Smad3/Snail signaling pathway, thus providing a potential target for the treatment of ESCC metastasis. |
| Databáze: | OpenAIRE |
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