HPSE enhancer RNA promotes cancer progression through driving chromatin looping and regulating hnRNPU/p300/EGR1/HPSE axis
HPSE enhancer RNA promotes cancer progression through driving chromatin looping and regulating hnRNPU/p300/EGR1/HPSE axis
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HPSE增强子RNA通过驱动染色质循环和调节hnRNPU/p300/EGR1/HPSE轴促进癌症进展
DOI：
10.1038/s41388-018-0128-0
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发表时间：
2018-05-01
期刊：
影响因子：
8
通讯作者：
Tong, Qiangsong
中科院分区：
文献类型：
--
作者：
Jiao, Wanju;Chen, Yajun;Tong, Qiangsong
最近的研究揭示了增强子RNA（eRNA）在基因表达中的新兴功能。然而，eRNA在调节乙酰肝素酶（HPSE）表达中的作用仍然是难以捉摸的，乙酰肝素酶是一种对癌症侵袭和转移至关重要的已建立的内切-β-D-葡萄糖醛酸酶。在此，通过对实验室可用的FANTOM 5表达图谱和染色质相互作用数据集的综合分析，我们鉴定了一种超级增强子及其衍生的eRNA，其促进了癌症中的HPSE表达（HPSE eRNA）。功能获得和功能丧失实验表明，HPSE eRNA促进体外和体内肿瘤发生和癌细胞的侵袭性。HPSE eRNA作为p300调控的核内非编码RNA，通过与核内不均一核糖核蛋白U（hnRNPU）结合，促进其与p300的相互作用，并富集在超级增强子上，导致超级增强子与HPSE启动子之间的染色质成环，p300介导转录因子早期生长反应1（EGR 1）的反式激活，从而提高HPSE的表达。此外，在HPSE过表达或沉默癌细胞中的拯救研究表明，HPSE eRNA通过驱动HPSE表达发挥致癌特性。在临床肿瘤组织中，HPSE eRNA呈高表达，与HPSE水平呈正相关，可作为肿瘤患者预后不良的独立预后因子。因此，这些发现表明HPSE eRNA作为一种新的非编码RNA，通过驱动染色质成环和调节hnRNPU/p300/EGR 1/HPSE轴促进癌症进展。
Recent studies reveal the emerging functions of enhancer RNAs (eRNAs) in gene expression. However, the roles of eRNAs in regulating the expression of heparanase (HPSE), an established endo-beta-D-glucuronidase essential for cancer invasion and metastasis, still remain elusive. Herein, through comprehensive analysis of publically available FANTOM5 expression atlas and chromatin interaction dataset, we identified a super enhancer and its derived eRNA facilitating the HPSE expression (HPSE eRNA) in cancers. Gain-of-function and loss-of-function experiments indicated that HPSE eRNA facilitated the in vitro and in vivo tumorigenesis and aggressiveness of cancer cells. Mechanistically, as a p300-regulated nuclear noncoding RNA, HPSE eRNA bond to heterogeneous nuclear ribonucleoprotein U (hnRNPU) to facilitate its interaction with p300 and their enrichment on super enhancer, resulting in chromatin looping between super enhancer and HPSE promoter, p300-mediated transactivation of transcription factor early growth response 1 (EGR1), and subsequent elevation of HPSE expression. In addition, rescue studies in HPSE overexpressing or silencing cancer cells indicated that HPSE eRNA exerted oncogenic properties via driving HPSE expression. In clinical cancer tissues, HPSE eRNA was highly expressed and positively correlated with HPSE levels, and served as an independent prognostic factor for poor outcome of cancer patients. Therefore, these findings indicate that as a novel noncoding RNA, HPSE eRNA promotes cancer progression through driving chromatin looping and regulating hnRNPU/p300/EGR1/HPSE axis.