State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine,Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
J Exp Clin Cancer Res. 2021 Mar 23;40(1):109. doi: 10.1186/s13046-021-01905-x.
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.
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.
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.
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.
远处转移是食管鳞状细胞癌（ESCC）的主要致死原因，其治疗选择有限，疗效不尽如人意。含溴结构域（BRD）的蛋白是癌症治疗的新兴靶点，具有良好的疗效。作为 BRD 家族的独特成员，ATAD2 在癌症发展中的功能和分子机制尚未得到充分研究。
分别在 75 名和 112 名 ESCC 患者中评估了 ATAD2 在 RNA 和蛋白质水平上的临床影响。通过体外和体内实验研究了 ATAD2 的生物学功能。通过 RNA 测序、荧光素酶报告基因检测、共免疫沉淀、染色质免疫沉淀、免疫荧光和 Western blot 实验鉴定了 ATAD2 的信号通路和下游效应物。
我们发现，ATAD2 表达水平升高与 ESCC 患者的淋巴结转移、临床分期较晚以及生存不良显著相关。沉默 ATAD2 显著抑制 ESCC 细胞的迁移和侵袭，抑制体内肿瘤生长和肺转移。机制上，我们鉴定出一个新的共因子 C/EBPβ。ATAD2 直接与 C/EBPβ相互作用，并促进其核转位，C/EBPβ 直接结合 TGF-β1 的启动子区域并激活其表达。进一步，我们证明 TGF-β1 通过 Smad3 依赖性方式激活其下游效应物。此外，我们还发现 ATAD2 通过 TGF-β 信号诱导的 Snail 表达和随后的上皮-间质转化促进 ESCC 转移。
我们的研究结果表明 ATAD2 具有促转移功能，并揭示了通过调节 C/EBPβ/TGF-β1/Smad3/Snail 信号通路的新分子机制，为 ESCC 转移的治疗提供了潜在靶点。
