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./nMethods: 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./nResults: 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./nConclusion: 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.

中文翻译：

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LncRNA DSCAM-AS1 与 YBX1 相互作用，通过形成激活 FOXA1 转录网络的正反馈回路促进癌症进展。

原理：叉头盒 A1 (FOXA1) 是乳腺癌、肺癌和前列腺癌发生和发展的关键转录因子。以前关于 FOXA1 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 FOXA1 致癌活性中的作用仍然未知。/n方法：癌症基因组图谱 (TCGA) 数据、RNA-seq 和 ChIP-seq 数据用于分析 FOXA1 调控的 lncRNA。RT-qPCR检测DSCAM-AS1的表达，RT-qPCR和Western blotting检测FOXA1、雌激素受体α（ERα）和Y盒结合蛋白1（YBX1）的表达。RNA pull-down 和 RIP-qPCR 被用来研究 DSCAM-AS1 和 YBX1 之间的相互作用。DSCAM-AS1 对恶性表型的影响通过体外和体内试验进行了检查。/n结果：在这项研究中，我们对 FOXA1 调控的 lncRNA 进行了全球分析。为了进行详细分析，我们选择了在肺腺癌、乳腺癌和前列腺癌中特异性表达的 lncRNA DSCAM-AS1。DSCAM-AS1 的表达水平受 FOXA1 驱动的两个超级增强子 (SE) 的调控。DSCAM-AS1 的高表达水平与预后不良有关。敲除实验表明 DSCAM-AS1 对异种移植肿瘤的生长至关重要。此外，我们证明了 DSCAM-AS1 可以调节主转录因子 FOXA1 的表达。在乳腺癌中，还发现 DSCAM-AS1 可调节 ERα。从机制上讲，DSCAM-AS1 与 YBX1 相互作用并影响 YBX1 在 FOXA1 和 ERα 启动子区域的募集。/n结论：我们的研究表明，lncRNA DSCAM-AS1 被 FOXA1 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-AS1 可以通过与 YBX1 相互作用并调节 FOXA1 和 ERα 的表达来促进癌症进展。