Abstract
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/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.ConclusionOur 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.
Highlights
Distant metastasis is the leading cause of death for esophageal squamous cell carcinoma (ESCC) with limited treatment options and unsatisfactory effectiveness
ATAD2 is upregulated in ESCC tissues and is associated with lymph node metastasis and advanced clinical stage To evaluate the expression difference between ESCC and normal esophageal tissues, we assessed ATAD2 mRNA and protein expression in ESCC and normal esophageal tissues. Quantitative real-time PCR (qRT-PCR) analysis detected significantly higher ATAD2 mRNA expression in cancer than normal tissues in 73 out of 83 paired tissues (Fig. 1a)
ATAD2 is an independent predictor of poor survival in ESCC patients We performed Kaplan–Meier analysis to identify the prognostic value of ATAD2 both at mRNA and protein level
Summary
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. Though surgery and/or chemoradiotherapy can be used as a curative intent for ESCC patients at early stage, most patients are diagnosed with advanced disease and what they confronted is less treatment options with unsatisfactory effectiveness. All of these highlight the imperative need for identification of new therapeutic targets for ESCC patients especially for those at advanced stage. Over 30 clinical trials have been carried out to evaluate the efficacy of BRD inhibitors and some of them have been proven to be effective, highlight that study of BRD proteins has far-reaching impact on cancer by hopeful clinical applications
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