METTL3稳定的超增强子-lncRNA SUCLG2-AS1在鼻咽癌转移和放射敏感性中介导SOX2的增强子和启动子之间形成长程染色质环联。
METTL3-stabilized super enhancers-lncRNA SUCLG2-AS1 mediates the formation of a long-range chromatin loop between enhancers and promoters of SOX2 in metastasis and radiosensitivity of nasopharyngeal carcinoma.
发表日期：2023 Sep
作者：
Xinyu Hu, Jianfeng Wu, Yong Feng, Hongxia Ma, Erbao Zhang, Chang Zhang, Qi Sun, Tingting Wang, Yizhi Ge, Dan Zong, Wei Chen, Xia He
来源：
Clinical and Translational Medicine
摘要：
超级增强子（super enhancers，SE）在细胞身份和发生疾病（包括肿瘤发生）中起着关键作用。SE相关的长非编码RNA转录本，也称为超级长非编码RNA（super-lncRNA），的消耗导致SE活性的失调。我们使用RNA测序、实时定量聚合酶链反应（RT-qPCR）和生物信息学筛选和鉴定了鼻咽癌（NPC）中升高的与转移相关的SE-lncRNA SUCLG2-AS1。利用西方印迹、RT-qPCR、甲基化RNA免疫沉淀（MeRIP）、RNA免疫沉淀、染色质免疫沉淀、RNA拉下和染色体构象捕获（3C）（染色体结构偶联测定）等方法进行了机制研究。SUCLG2-AS1与不良预后相关。SUCLG2-AS1在体外和体内促进了NPC细胞的侵袭和转移，同时抑制了凋亡和放射敏感性。机制上，SUCLG2-AS1高表达以m6A依赖的方式出现。发现SUCLG2-AS1位于SOX2的SE区域，通过长程染色质环形结构形成调控了SOX2的表达，该结构通过介导转录因子CTCF占据了SOX2的SE和启动子区域，从而调节了NPC的转移和放射敏感性。综上所述，我们的数据表明SUCLG2-AS1可能作为鼻咽癌的临床治疗的新干预靶点。©2023作者。由上海临床生物信息学研究所代表约翰·威利·扬有限责任公司出版的《临床转化医学》发布。
Super enhancers (SE) play pivotal roles in cell identity and diseases occur including tumorigenesis. The depletion of SE-associated lncRNA transcripts, also known as super-lncRNA, causes the activity of SE to be dysregulated.We screened and identified an elevated metastasis-associated SE-lncRNA SUCLG2-AS1 in nasopharyngeal carcinoma (NPC) using RNA-sequencing, real-time quantitative polymerase chain reaction (RT-qPCR) and bioinformatics. Western blotting, RT-qPCR, methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation, chromatin immunoprecipitation, RNA pull-down and 3C (chromosome conformation capture assays) were used for mechanistic studies.SUCLG2-AS1 was correlated with a poor prognosis. SUCLG2-AS1 promotes NPC cell invasion and metastasis while repressing apoptosis and radiosensitivity in vitro and in vivo. Mechanistically, high SUCLG2-AS1 expression occurred in an m6A-dependent manner. SUCLG2-AS1 was found to be located in the SE region of SOX2, and it regulated the expression of SOX2 via long-range chromatin loop formation, which via mediating CTCF (transcription factor) occupied the SE and promoter region of SOX2, thus regulating the metastasis and radiosensitivity of NPC.Taken together, our data suggest that SUCLG2-AS1 may serve as a novel intervention target for the clinical treatment of NPC.© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.