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超级增强子相关的 TMEM44-AS1 通过与 Myc 形成正反馈环加剧了神经胶质瘤的进展。

Super-enhancer-associated TMEM44-AS1 aggravated glioma progression by forming a positive feedback loop with Myc.

机构信息

Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.

Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, 230601, China.

出版信息

J Exp Clin Cancer Res. 2021 Oct 25;40(1):337. doi: 10.1186/s13046-021-02129-9.

DOI:10.1186/s13046-021-02129-9
PMID:34696771
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8543865/
Abstract

BACKGROUND

Long non-coding RNAs (lncRNAs) have been considered as one type of gene expression regulator for cancer development, but it is not clear how these are regulated. This study aimed to identify a specific lncRNA that promotes glioma progression.

METHODS

RNA sequencing (RNA-seq) and quantitative real-time PCR were performed to screen differentially expressed genes. CCK-8, transwell migration, invasion assays, and a mouse xenograft model were performed to determine the functions of TMEM44-AS1. Co-IP, ChIP, Dual-luciferase reporter assays, RNA pulldown, and RNA immunoprecipitation assays were performed to study the molecular mechanism of TMEM44-AS1 and the downstream target.

RESULTS

We identified a novel lncRNA TMEM44-AS1, which was aberrantly expressed in glioma tissues, and that increased TMEM44-AS1 expression was correlated with malignant progression and poor survival for patients with glioma. Expression of TMEM44-AS1 increased the proliferation, colony formation, migration, and invasion of glioma cells. Knockdown of TMEM44-AS1 in glioma cells reduced cell proliferation, colony formation, migration and invasion, and tumor growth in a nude mouse xenograft model. Mechanistically, TMEM44-AS1 is directly bound to the SerpinB3, and sequentially activated Myc and EGR1/IL-6 signaling; Myc transcriptionally induced TMEM44-AS1 and directly bound to the promoter and super-enhancer of TMEM44-AS1, thus forming a positive feedback loop with TMEM44-AS. Further studies demonstrated that Myc interacts with MED1 regulates the super-enhancer of TMEM44-AS1. More importantly, a novel small-molecule Myc inhibitor, Myci975, alleviated TMEM44-AS1-promoted the growth of glioma cells.

CONCLUSIONS

Our study implicates a crucial role of the TMEM44-AS1-Myc axis in glioma progression and provides a possible anti-glioma therapeutic agent.

摘要

背景

长链非编码 RNA（lncRNA）被认为是癌症发展的一种基因表达调控因子，但这些调控因子的调控机制尚不清楚。本研究旨在鉴定一种促进神经胶质瘤进展的特定 lncRNA。

方法

采用 RNA 测序（RNA-seq）和实时定量 PCR 筛选差异表达基因。通过 CCK-8 法、transwell 迁移、侵袭实验和小鼠异种移植模型来确定 TMEM44-AS1 的功能。通过 Co-IP、ChIP、双荧光素酶报告基因检测、RNA 下拉和 RNA 免疫沉淀实验来研究 TMEM44-AS1 及其下游靶基因的分子机制。

结果

我们鉴定了一种新型 lncRNA TMEM44-AS1，其在神经胶质瘤组织中异常表达，并且 TMEM44-AS1 表达的增加与神经胶质瘤患者的恶性进展和不良预后相关。TMEM44-AS1 的表达增加了神经胶质瘤细胞的增殖、集落形成、迁移和侵袭。在神经胶质瘤细胞中敲低 TMEM44-AS1 可降低细胞增殖、集落形成、迁移和侵袭以及裸鼠异种移植模型中的肿瘤生长。机制上，TMEM44-AS1 直接与 SerpinB3 结合，随后激活 Myc 和 EGR1/IL-6 信号通路；Myc 转录激活 TMEM44-AS1，并直接结合 TMEM44-AS1 的启动子和超级增强子，从而与 TMEM44-AS 形成正反馈回路。进一步的研究表明，Myc 与 MED1 相互作用调节 TMEM44-AS1 的超级增强子。更重要的是，一种新型的 Myc 小分子抑制剂 Myci975 可减轻 TMEM44-AS1 促进神经胶质瘤细胞生长的作用。

结论

本研究表明 TMEM44-AS1-Myc 轴在神经胶质瘤进展中起关键作用，并为神经胶质瘤的治疗提供了一种潜在的药物。

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