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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Metastasis | Research

ATAD2 interacts with C/EBPβ to promote esophageal squamous cell carcinoma metastasis via TGF-β1/Smad3 signaling

Authors: Lian-Jing Cao, Yi-Jun Zhang, Si-Qi Dong, Xi-Zhao Li, Xia-Ting Tong, Dong Chen, Zi-Yi Wu, Xiao-Hui Zheng, Wen-Qiong Xue, Wei-Hua Jia, Jiang-Bo Zhang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

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.

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Title: ATAD2 interacts with C/EBPβ to promote esophageal squamous cell carcinoma metastasis via TGF-β1/Smad3 signaling
Authors: Lian-Jing Cao
Yi-Jun Zhang
Si-Qi Dong
Xi-Zhao Li
Xia-Ting Tong
Dong Chen
Zi-Yi Wu
Xiao-Hui Zheng
Wen-Qiong Xue
Wei-Hua Jia
Jiang-Bo Zhang
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Metastasis
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01905-x

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