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HPSE enhancer RNA promotes cancer progression through driving chromatin looping and regulating hnRNPU/p300/EGR1/HPSE axis

Oncogene volume 37, pages 2728–2745 (2018)Cite this article

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Abstract

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-β-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.

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Acknowledgements

We appreciate Dr. Tso-Pang Yao for providing vectors. This work was granted by the National Natural Science Foundation of China (81272779, 81372667, 81472363, 81402301, 81402408, 81572423, 81672500, 81773094, and 81772967), and Natural Science Foundation of Hubei Province (2014CFA012).

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  1. These authors contributed equally: W. Jiao, Y. Chen, H. Song and D. Li.

Authors and Affiliations

  1. Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Wanju Jiao, Yajun Chen & Liduan Zheng

  2. Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Huajie Song, Dan Li, Hong Mei, Feng Yang, Erhu Fang, Xiaojing Wang & Qiangsong Tong

  3. Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Kai Huang, Liduan Zheng & Qiangsong Tong

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  1. Wanju Jiao
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Jiao, W., Chen, Y., Song, H. et al. HPSE enhancer RNA promotes cancer progression through driving chromatin looping and regulating hnRNPU/p300/EGR1/HPSE axis. Oncogene 37, 2728–2745 (2018). https://doi.org/10.1038/s41388-018-0128-0

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