Esophageal cancer (ESCA) is one of the most common cancers worldwide and has a very poor prognosis. Hypoxia-inducible factor 1 (HIF1) signaling pathway plays a critical role in tumorigenesis and is therefore considered a potential therapeutic target in the treatment of many cancers. Activating transcription factor 5 (ATF5) facilitates the expression of various genes and has been extensively studied for its potential role in cancer treatment. The expression level of ATF5 in clinic sample was detected by quantitative real time PCR and immunohistochemistry. ATF5 biological function was investigated by western blot, cell cycle analysis, cell viability assay, luciferase reporter assays, colony formation assay, transwell assay, wound healing assay, tube formation assay, and ELISA assay. CHIP and Re-CHIP assay, GST-pulldown, and RNA-sequencing were used to study the cross-talks between ATF5 and HIF1 complex. Mouse xenograft study was utilized to study the correlation of ATF5 and tumor growth in vivo. Student’s t-test or Chi-square test was used for statistical analysis. Here, we first found ATF5 was dramatically upregulated in ESCA cancer and related with poor survival time. Next, we found that the expression level of ATF5 had a positive relationship with the proliferation, migration, and invasion ability of ESCA cells. Besides, we innovatively found that ATF5 functions as a novel coactivator in HIF1 transcription complex by binding to HIF1α. Further, we demonstrated that silencing ATF5 phenocopies HIF1α knockdown in tumorigenic properties in vitro and inhibited ESCA tumor angiogenesis and proliferation in vivo. Herein, we found ATF5 as a novel component of the HIF1 transcription complex. The findings of the present study may provide new insights into the development of a novel and more efficient therapeutic strategy against ESCA.

中文翻译：

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ATF5和HIF1α协同激活食管癌中的HIF1信号通路

食管癌（ESCA）是世界范围内最常见的癌症之一，预后极差。缺氧诱导因子 1 (HIF1) 信号通路在肿瘤发生中起关键作用，因此被认为是治疗许多癌症的潜在治疗靶点。激活转录因子 5 (ATF5) 促进各种基因的表达，并因其在癌症治疗中的潜在作用而被广泛研究。通过定量实时PCR和免疫组织化学检测临床样本中ATF5的表达水平。通过蛋白质印迹、细胞周期分析、细胞活力测定、荧光素酶报告基因测定、集落形成测定、transwell 测定、伤口愈合测定、管形成测定和 ELISA 测定研究 ATF5 生物学功能。CHIP 和 Re-CHIP 检测，GST 下拉，和 RNA 测序用于研究 ATF5 和 HIF1 复合物之间的串扰。小鼠异种移植研究用于研究 ATF5 与体内肿瘤生长的相关性。学生 t 检验或卡方检验用于统计分析。在这里，我们首先发现 ATF5 在 ESCA 癌症中显着上调，并且与较差的存活时间有关。接下来，我们发现ATF5的表达水平与ESCA细胞的增殖、迁移和侵袭能力呈正相关。此外，我们创新性地发现 ATF5 通过与 HIF1α 结合，在 HIF1 转录复合物中作为一种新的共激活因子发挥作用。此外，我们证明沉默 ATF5 表型在体外抑制 HIF1α 的致瘤特性，并在体内抑制 ESCA 肿瘤血管生成和增殖。在此处，我们发现 ATF5 是 HIF1 转录复合物的一个新成分。本研究的结果可能为开发一种新的、更有效的针对 ESCA 的治疗策略提供新的见解。