Super-enhancer-driven lncRNA LIMD1-AS1 activated by CDK7 promotes glioma progression.
Super-enhancer-driven lncRNA LIMD1-AS1 activated by CDK7 promotes glioma progression.
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DOI：
10.1038/s41419-023-05892-z
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发表时间：
2023-06-29
影响因子：
9
通讯作者：
Bian, Erbao
中科院分区：
文献类型：
--
作者：
Chen, Zhigang;Tian, Dasheng;Chen, Xueran;Cheng, Meng;Xie, Han;Zhao, JiaJia;Liu, Jun;Fang, Zhiyou;Zhao, Bing;Bian, Erbao
长链非编码RNA（lncRNA）是组织特异性表达模式，在癌症中失调。如何监管仍有待确定。我们的目的是研究胶质瘤特异性lncRNA LIMD1-AS1在超增强子（super-enhancer，SE）激活下的功能并探讨其可能的机制。在本文中，我们确定了SE驱动的lncRNA，LIMD1-AS1，这是在胶质瘤中的表达水平显着高于正常脑组织。高LIMD1-AS1水平与胶质瘤患者的生存时间显著相关。LIMD1-AS1过表达显著增强胶质瘤细胞的增殖、集落形成、迁移和侵袭，而LIMD1-AS1敲低抑制胶质瘤细胞的增殖、集落形成、迁移和侵袭以及胶质瘤细胞的异种移植瘤生长。从机制上讲，CDK7的抑制显著减弱了MED 1向LIMD1-AS 1的超级增强子的募集，然后降低了LIMD1-AS 1的表达。最重要的是，LIMD1-AS1可以直接与HSPA5结合，导致干扰素信号转导的激活。我们的研究结果支持CDK7介导的LIMD1-AS1表观遗传学激活在胶质瘤进展中起关键作用的观点，并为胶质瘤患者提供了一种有希望的治疗方法。
Long non-coding RNAs (lncRNAs) are tissue-specific expression patterns and dysregulated in cancer. How they are regulated still needs to be determined. We aimed to investigate the functions of glioma-specific lncRNA LIMD1-AS1 activated by super-enhancer (SE) and identify the potential mechanisms. In this paper, we identified a SE-driven lncRNA, LIMD1-AS1, which is expressed at significantly higher levels in glioma than in normal brain tissue. High LIMD1-AS1 levels were significantly associated with a shorter survival time of glioma patients. LIMD1-AS1 overexpression significantly enhanced glioma cells proliferation, colony formation, migration, and invasion, whereas LIMD1-AS1 knockdown inhibited their proliferation, colony formation, migration, and invasion, and the xenograft tumor growth of glioma cells in vivo. Mechanically, inhibition of CDK7 significantly attenuates MED1 recruitment to the super-enhancer of LIMD1-AS1 and then decreases the expression of LIMD1-AS1. Most importantly, LIMD1-AS1 could directly bind to HSPA5, leading to the activation of interferon signaling. Our findings support the idea that CDK7 mediated-epigenetically activation of LIMD1-AS1 plays a crucial role in glioma progression and provides a promising therapeutic approach for patients with glioma.
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