ATF3 downmodulates its new targets IFI6 and IFI27 to suppress the growth and migration of tongue squamous cell carcinoma cells.
ATF3 downmodulates its new targets IFI6 and IFI27 to suppress the growth and migration of tongue squamous cell carcinoma cells.
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ATF3下调其新靶点IFI6和IFI27抑制舌鳞状细胞癌细胞的生长和迁移
DOI：
10.1371/journal.pgen.1009283
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发表时间：
2021-03
期刊：
影响因子：
4.5
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Xu L;Zu T;Li T;Li M;Mi J;Bai F;Liu G;Wen J;Li H;Brakebusch C;Wang X;Wu X
转录激活因子3（Activating transcription factor 3，ATF 3）是参与调节细胞应激反应的关键转录因子，在不同组织中具有不同的表达水平和功能。ATF 3也被证明在调节肿瘤的发展和进展中起着至关重要的作用，但其在口腔鳞状细胞癌中的潜在作用尚未得到充分研究。在这项研究中，我们检查了舌鳞状细胞癌（TSCC）的活检组织，发现ATF 3的核表达水平与TSCC的分化状态呈负相关，这是通过分析ATGC数据库验证。通过使用ATF 3在四种不同TSCC细胞系中的功能获得或丧失分析，我们证明了ATF 3在体外负调控人TSCC细胞的生长和迁移。RNA-seq分析鉴定了ATF 3的两个新的下游靶点，干扰素α诱导蛋白6（IFI 6）和27（IFI 27），它们在ATF 3缺失的细胞中上调，在ATF 3过表达的细胞中下调。染色质免疫沉淀分析表明，ATF 3结合的IFI 6和IFI 27基因的启动子区。IFI 6和IFI 27在TSCC活检组织中均高度表达，并且TSCC细胞中IFI 6或IFI 27的敲低阻断了由ATF 3缺失诱导的细胞生长和迁移。相反，IFI 6或IFI 27的过表达抵消了由ATF 3的过表达诱导的TSCC细胞生长和迁移的抑制。最后，小鼠体内研究证实了这些体外研究结果。我们的研究表明，ATF 3通过其下游靶点IFI 6和IFI 27的负调控在TSCC中发挥抗肿瘤作用。
Activating transcription factor 3 (ATF3) is a key transcription factor involved in regulating cellular stress responses, with different expression levels and functions in different tissues. ATF3 has also been shown to play crucial roles in regulating tumor development and progression, however its potential role in oral squamous cell carcinomas has not been fully explored. In this study, we examined biopsies of tongue squamous cell carcinomas (TSCCs) and found that the nuclear expression level of ATF3 correlated negatively with the differentiation status of TSCCs, which was validated by analysis of the ATGC database. By using gain- or loss- of function analyses of ATF3 in four different TSCC cell lines, we demonstrated that ATF3 negatively regulates the growth and migration of human TSCC cells in vitro. RNA-seq analysis identified two new downstream targets of ATF3, interferon alpha inducible proteins 6 (IFI6) and 27 (IFI27), which were upregulated in ATF3-deleted cells and were downregulated in ATF3-overexpressing cells. Chromatin immunoprecipitation assays showed that ATF3 binds the promoter regions of the IFI6 and IFI27 genes. Both IFI6 and IFI27 were highly expressed in TSCC biopsies and knockdown of either IFI6 or IFI27 in TSCC cells blocked the cell growth and migration induced by the deletion of ATF3. Conversely, overexpression of either IFI6 or IFI27 counteracted the inhibition of TSCC cell growth and migration induced by the overexpression of ATF3. Finally, an in vivo study in mice confirmed those in vitro findings. Our study suggests that ATF3 plays an anti-tumor function in TSCCs through the negative regulation of its downstream targets, IFI6 and IFI27.
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DOI：
10.1186/s13046-018-0919-8
发表时间：
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期刊：
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