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

BackgroundDistant 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.MethodsThe 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.ResultsWe 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/EBP beta. ATAD2 directly interacted with C/EBP beta and promoted its nuclear translocation, which directly bound to the promoter region of TGF-beta 1 and activated its expression. Further, we demonstrated that TGF-beta 1 activated its downstream effectors in a Smad3 dependent manner. In addition, we further found that ATAD2 promoted ESCC metastasis through TGF-beta signaling induced Snail expression and the subsequent epithelial-mesenchymal transition.ConclusionOur findings demonstrated the pro-metastatic function of ATAD2 and uncovered the new molecular mechanism by regulating C/EBP beta /TGF-beta 1/Smad3/Snail signaling pathway, thus providing a potential target for the treatment of ESCC metastasis.

Automated summary

The study found that elevated ATAD2 expression was significantly associated with lymph node metastasis, advanced clinical stage, and poor survival of ESCC patients. ATAD2 promotes ESCC metastasis through regulating the C/EBP beta /TGF-beta 1/Smad3/Snail signaling pathway.