LncRNA DSCAM-AS1 interacts with YBX1 to promote cancer progression by forming a positive feedback loop that activates FOXA1 transcription network
LncRNA DSCAM-AS1 interacts with YBX1 to promote cancer progression by forming a positive feedback loop that activates FOXA1 transcription network
复制标题
LncRNA DSCAM-AS1 与 YBX1 相互作用，通过形成激活 FOXA1 转录网络的正反馈环来促进癌症进展
DOI：
10.7150/thno.47830
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Yin, Dong
中科院分区：
文献类型：
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作者：
Zhang, Yin;Huang, Yong-Xin;Yin, Dong
FOXA 1是乳腺癌、肺癌和前列腺癌发生发展过程中的重要转录因子。以往对FOXA 1转录网络的研究主要集中在蛋白质编码基因上。其长链非编码RNA（lncRNA）的调控网络及其在FOXA 1致癌活性中的作用仍然未知。方法：利用TCGA数据库、RNA-seq和ChIP-seq数据库分析FOXA 1调控的lncRNA。RT-qPCR检测DSCAM-AS 1的表达，RT-qPCR和Western blotting检测FOXA 1、雌激素受体α（ERα）和Y盒结合蛋白1（YBX 1）的表达。采用RNA pull-down和RIP-qPCR方法研究DSCAM-AS 1与YBX 1的相互作用。通过体外和体内试验检测DSCAM-AS 1对恶性表型的影响。结果：在这项研究中，我们对FOXA 1调控的lncRNA进行了全面分析。为了进行详细分析，我们选择了lncRNA DSCAM-AS 1，它在肺腺癌、乳腺癌和前列腺癌中特异性表达。DSCAM-AS 1的表达水平由FOXA 1驱动的两个超级增强子（SE）调节。DSCAM-AS 1高表达与预后不良相关。敲除实验表明DSCAM-AS 1对于异种移植肿瘤的生长是必需的。此外，我们证明DSCAM-AS 1可以调节主转录因子FOXA 1的表达。在乳腺癌中，DSCAM-AS 1也被发现调节ERα。在机制上，DSCAM-AS 1与YBX 1相互作用并影响YBX 1在FOXA 1和ERα启动子区的募集。结论：我们的研究表明，lncRNA DSCAM-AS 1被FOXA 1驱动的超级增强子转录激活，并表现出谱系特异性表达模式。DSCAM-AS 1可通过与YBX 1相互作用，调节FOXA 1和ERα的表达，从而促进肿瘤的进展。
Rationale: The forkhead box A1 (FOXA1) is a crucial transcription factor in initiation and development of breast, lung and prostate cancer. Previous studies about the FOXA1 transcriptional network were mainly focused on protein-coding genes. Its regulatory network of long non-coding RNAs (lncRNAs) and their role in FOXA1 oncogenic activity remains unknown. Methods: The Cancer Genome Atlas (TCGA) data, RNA-seq and ChIP-seq data were used to analyze FOXA1 regulated lncRNAs. RT-qPCR was used to detect the expression of DSCAM-AS1, RT-qPCR and Western blotting were used to determine the expression of FOXA1, estrogen receptor α (ERα) and Y box binding protein 1 (YBX1). RNA pull-down and RIP-qPCR were employed to investigate the interaction between DSCAM-AS1 and YBX1. The effect of DSCAM-AS1 on malignant phenotypes was examined through in vitro and in vivo assays. Results: In this study, we conducted a global analysis of FOXA1 regulated lncRNAs. For detailed analysis, we chose lncRNA DSCAM-AS1, which is specifically expressed in lung adenocarcinoma, breast and prostate cancer. The expression level of DSCAM-AS1 is regulated by two super-enhancers (SEs) driven by FOXA1. High expression levels of DSCAM-AS1 was associated with poor prognosis. Knockout experiments showed DSCAM-AS1 was essential for the growth of xenograft tumors. Moreover, we demonstrated DSCAM-AS1 can regulate the expression of the master transcriptional factor FOXA1. In breast cancer, DSCAM-AS1 was also found to regulate ERα. Mechanistically, DSCAM-AS1 interacts with YBX1 and influences the recruitment of YBX1 in the promoter regions of FOXA1 and ERα. Conclusion: Our study demonstrated that lncRNA DSCAM-AS1 was transcriptionally activated by super-enhancers driven by FOXA1 and exhibited lineage-specific expression pattern. DSCAM-AS1 can promote cancer progression by interacting with YBX1 and regulating expression of FOXA1 and ERα.