超级增强子驱动“CYTOR-FOSL1正反馈环路”促进口腔鳞癌Tumor budding转移的研究

超级增强子（Super enhancers, SEs）是具有调控转录活性的超长顺式作用元件，能够驱动决定肿瘤细胞身份基因的表达。我们前期研究证实Tumor budding（TB）是口腔鳞癌中具有高转移潜能的癌细胞亚群，受FOSL1激活的SEs调控；进一步研究提示TB中上调的核心长链非编码RNA CYTOR可结合SEs，促进FOSL1表达，并受FOSL1及SEs调控；据此，我们提出SEs可驱动CYTOR-FOSL1形成正反馈环路，决定TB的身份及转移表型。本课题拟在上述工作基础上，基于染色质免疫共沉淀、RNA纯化染色质分离和环状染色质构象捕获技术，阐明CYTOR结合SEs调控FOSL1促进口腔鳞癌TB转移的机制；探讨CYTOR的SEs与启动子及FOSL1的关系，揭示FOSL1调控CYTOR的机制。本项目有望揭示CYOTR上、下游调控的新机制，为靶向TB治疗口腔鳞癌提供新的靶点。

Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive expression of genes that define cell identity. Increasing evidences implicate that SEs are central to the maintenance of cancer cell identity and promote oncogenic transcription in tumorigenesis and progression. In our previous studies, we confirmed that tumor budding defined a sub-population cancer cells with high aggressiveness and metastatic potentials, then revealed that FOSL1 promoted metastasis of tumor budding cells through activating SEs-dependent transcriptional program in oral squamous cell carcinoma (OSCC). Notably, we also observed that lncRNA CYTOR was increased in tumor budding of OSCC and might bind to the SE of FOSL1 to promote its transcription. Moreover, ChIP-seq and qPCR data indicated that CYTOR was controlled by SEs and FOSL1. These findings suggest that CYTOR-FOSL1 regulatory circuit driven by SEs promotes metastasis of tumor budding cells in OSCC. In this project, we aim to investigate the functional role of CYTOR, explore its potential mechanisms and clarify the relationship of CYTOR, SE and FOSL1 in OSCC. This study will identify a DNA/RNA/protein complex which activates FOSL1-CYTOR circuit and promotes metastasis of tumor budding in OSCC, broadening our understanding of transcription dysregulation mediated by master transcription factors, lncRNAs and SEs.