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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References
Hulett MD, Freeman C, Hamdorf BJ, Baker RT, Harris MJ, Parish CR. Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. Nat Med. 1999;5:803–9.
Gingis-Velitski S, Zetser A, Flugelman MY, Vlodavsky I, Ilan N. Heparanase induces endothelial cell migration via protein kinase B/Akt activation. J Biol Chem. 2004;279:23536–41.
Zetser A, Bashenko Y, Miao HQ, Vlodavsky I, Ilan N. Heparanase affects adhesive and tumorigenic potential of human glioma cells. Cancer Res. 2003;63:7733–41.
Shinyo Y, Kodama J, Hongo A, Yoshinouchi M, Hiramatsu Y. Heparanase expression is an independent prognostic factor in patients with invasive cervical cancer. Ann Oncol. 2003;14:1505–10.
Valentina M, Maria Francesca S, Giovanni G, Maurizio O. Heparanase as a target in cancer therapy. Curr Cancer Drug Targets. 2014;14:286–93.
Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, et al. An atlas of active enhancers across human cell types and tissues. Nature. 2014;507:455–61.
Rada-Iglesias A, Bajpai R, Swigut T, Brugmann SA, Flynn RA, Wysocka J. A unique chromatin signature uncovers early developmental enhancers in humans. Nature. 2011;470:279–83.
Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA et al. Transcriptional super-enhancers connected to cell identity and disease. Cell. 2013; 155: https://doi.org/10.1016/j.cell.2013.1009.1053.
Kim TK, Hemberg M, Gray JM, Costa AM, Bear DM, Wu J, et al. Widespread transcription at neuronal activity-regulated enhancers. Nature. 2010;465:182–7.
He B, Chen C, Teng L, Tan K. Global view of enhancer–promoter interactome in human cells. Proc Natl Acad Sci USA. 2014;111:E2191–E2199.
Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, et al. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.
Stadlmann S, Moser PL, Pollheimer J, Steiner P, Krugmann J, Dirnhofer S, et al. Heparanase-1 gene expression in normal, hyperplastic and neoplastic prostatic tissue. Eur J Cancer. 2003;39:2229–33.
El-Assal ON, Yamanoi A, Ono T, Kohno H, Nagasue N. The clinicopathological significance of heparanase and basic fibroblast growth factor expressions in hepatocellular carcinoma. Clin Cancer Res. 2001;7:1299–305.
Takaoka M, Naomoto Y, Ohkawa T, Uetsuka H, Shirakawa Y, Uno F, et al. Heparanase expression correlates with invasion and poor prognosis in gastric cancers. Lab Invest. 2003;83:613–22.
Wang L, Park HJ, Dasari S, Wang S, Kocher JP, Li W. CPAT: Coding-Potential Assessment Tool using an alignment-free logistic regression model. Nucleic Acids Res. 2013;41:e74.
Hsieh CL, Fei T, Chen Y, Li T, Gao Y, Wang X, et al. Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proc Natl Acad Sci USA. 2014;111:7319–24.
Ogishima T, Shiina H, Breault JE, Terashima M, Honda S, Enokida H, et al. Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer. Oncogene. 2005;24:6765–72.
de Mestre AM, Rao S, Hornby JR, Soe-Htwe T, Khachigian LM, Hulett MD. Early growth response gene 1 (egr1) regulates heparanase gene transcription in tumor cells. J Biol Chem. 2005;280:35136–47.
Silverman ES, Du J, Williams AJ, Wadgaonkar R, Drazen JM, Collins T. cAMP-response- element-binding-protein-binding protein (CBP) and p300 are transcriptional co-activators of early growth response factor-1 (Egr-1). Biochem J. 1998;336:183–9.
Zetser A, Bashenko Y, Edovitsky E, Levy-Adam F, Vlodavsky I, Ilan N. Heparanase induces vascular endothelial growth factor expression: correlation with p38 phosphorylation levels and Src activation. Cancer Res. 2006;66:1455–63.
Zheng L, Jiao W, Song H, Qu H, Li D, Mei H, et al. miRNA-558 promotes gastric cancer progression through attenuating Smad4-mediated repression of heparanase expression. Cell Death Dis. 2016;7:e2382.
Li W, Notani D, Ma Q, Tanasa B, Nunez E, Chen AY, et al. Functional importance of eRNAs for estrogen-dependent transcriptional activation events. Nature. 2013;498:516–20.
Melo CA, Drost J, Wijchers PJ, van de Werken H, de Wit E, Oude Vrielink JA, et al. eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol Cell. 2013;49:524–35.
Fairbanks MB, Mildner AM, Leone JW, Cavey GS, Mathews WR, Drong RF, et al. Processing of the human heparanase precursor and evidence that the active enzyme is a heterodimer. J Biol Chem. 1999;274:29587–90.
Abboud-Jarrous G, Rangini-Guetta Z, Aingorn H, Atzmon R, Elgavish S, Peretz T, et al. Site-directed mutagenesis, proteolytic cleavage, and activation of human proheparanase. J Biol Chem. 2005;280:13568–75.
Roshon MJ, Ruley HE. Hypomorphic mutation in hnRNP U results in post-implantation lethality. Transgenic Res. 2005;14:179–92.
Puvvula PK, Desetty RD, Pineau P, Marchio A, Moon A, Dejean A, et al. Long noncoding RNA PANDA and scaffold-attachment-factor SAFA control senescence entry and exit. Nat Commun. 2014;5:5323.
Matsuoka Y, Uehara N, Tsubura A. hnRNP U interacts with the c-Myc-Max complex on the E-box promoter region inducing the ornithine decarboxylase gene. Oncol Rep. 2009;22:249–55.
Bi HS, Yang XY, Yuan JH, Yang F, Xu D, Guo YJ, et al. H19 inhibits RNA polymerase II-mediated transcription by disrupting the hnRNP U–actin complex. Biochim Biophys Acta. 2013;1830:4899–906.
Mattern KA, van der Kraan I, Schul W, de Jong L, van Driel R. Spatial organization of four hnrnp proteins in relation to sites of transcription, to nuclear speckles, and to each other in interphase nuclei and nuclear matrices of HeLa cells. Exp Cell Res. 1999;246:461–70.
Kiledjian M, Dreyfuss G. Primary structure and binding activity of the hnRNP U protein: binding RNA through RGG box. EMBO J. 1992;11:2655–64.
Iyer NG, Ozdag H, Caldas C. p300//CBP and cancer. Oncogene. 2004;23:4225–31.
Dai P, Akimaru H, Tanaka Y, Hou DX, Yasukawa T, Kanei-Ishii C, et al. CBP as a transcriptional coactivator of c-Myb. Genes Dev. 1996;10:528–40.
Lee JS, See RH, Galvin KM, Wang J, Shi Y. Functional interactions between YY1 and adenovirus E1A. Nucleic Acids Res. 1995;23:925–31.
Kim YW, Kim A. Histone acetylation contributes to chromatin looping between the locus control region and globin gene by influencing hypersensitive site formation. Biochim Biophys Acta. 2013;1829:963–9.
Fang F, Xu Y, Chew KK, Chen X, Ng HH, Matsudaira P. Coactivators p300 and CBP maintain the identity of mouse embryonic stem cells by mediating long-range chromatin structure. Stem Cells. 2014;32:1805–16.
Fahmy RG, Dass CR, Sun LQ, Chesterman CN, Khachigian LM. Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth. Nat Med. 2003;9:1026–32.
Hagege H, Klous P, Braem C, Splinter E, Dekker J, Cathala G, et al. Quantitative analysis of chromosome conformation capture assays (3C-qPCR). Nat Protoc. 2007;2:1722–33.
Zhao X, Li D, Pu J, Mei H, Yang D, Xiang X, et al. CTCF cooperates with noncoding RNA MYCNOS to promote neuroblastoma progression through facilitating MYCN expression. Oncogene. 2016;35:3565–76.
Zhang H, Pu J, Qi T, Qi M, Yang C, Li S, et al. MicroRNA-145 inhibits the growth, invasion, metastasis and angiogenesis of neuroblastoma cells through targeting hypoxia-inducible factor 2 alpha. Oncogene. 2014;33:387–97.
Zheng L, Qi T, Yang D, Qi M, Li D, Xiang X, et al. microRNA-9 suppresses the proliferation, invasion and metastasis of gastric cancer cells through targeting cyclin D1 and Ets1. PLoS ONE. 2013;8:e55719.
Zheng L, Pu J, Qi T, Qi M, Li D, Xiang X, et al. miRNA-145 targets v-ets erythroblastosis virus E26 oncogene homolog 1 to suppress the invasion, metastasis, and angiogenesis of gastric cancer cells. Mol Cancer Res. 2013;11:182–93.
Zheng L, Jiao W, Mei H, Song H, Li D, Xiang X, et al. miRNA-337-3p inhibits gastric cancer progression through repressing myeloid zinc finger 1-facilitated expression of matrix metalloproteinase 14. Oncotarget. 2016;7:40314–28.
Jiang G, Zheng L, Pu J, Mei H, Zhao J, Huang K, et al. Small RNAs targeting transcription start site induce heparanase silencing through interference with transcription initiation in human cancer cells. PLoS ONE. 2012;7:e31379.
Li D, Mei H, Qi M, Yang D, Zhao X, Xiang X, et al. FOXD3 is a novel tumor suppressor that affects growth, invasion, metastasis and angiogenesis of neuroblastoma. Oncotarget. 2013;4:2021–44.
Li D, Zhao X, Xiao Y, Mei H, Pu J, Xiang X, et al. Intelectin 1 suppresses tumor progression and is associated with improved survival in gastric cancer. Oncotarget. 2015;6:16168–82.
Li D, Mei H, Pu J, Xiang X, Zhao X, Qu H, et al. Intelectin 1 suppresses the growth, invasion and metastasis of neuroblastoma cells through up-regulation of N-myc downstream regulated gene 2. Mol Cancer. 2015;14:47.
Xiang X, Zhao X, Qu H, Li D, Yang D, Pu J, et al. Hepatocyte nuclear factor 4 alpha promotes the invasion, metastasis and angiogenesis of neuroblastoma cells via targeting matrix metalloproteinase 14. Cancer Lett. 2015;359:187–97.
Ito A, Lai CH, Zhao X, Si Saito, Hamilton MH, Appella E, et al. p300/CBP- mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J. 2001;20:1331–40.
Qu H, Zheng L, Pu J, Mei H, Xiang X, Zhao X, et al. miRNA-558 promotes tumorigenesis and aggressiveness of neuroblastoma cells through activating the transcription of heparanase. Hum Mol Genet. 2015;24:2539–51.
Qu H, Zheng L, Jiao W, Mei H, Li D, Song H, et al. Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase. Sci Rep. 2016;6:32628.
Zheng L, Li D, Xiang X, Tong L, Qi M, Pu J, et al. Methyl jasmonate abolishes the migration, invasion and angiogenesis of gastric cancer cells through down-regulation of matrix metalloproteinase 14. BMC Cancer. 2013;13:74.
Zheng L, Jiang G, Mei H, Pu J, Dong J, Hou X, et al. Small RNA interference-mediated gene silencing of heparanase abolishes the invasion, metastasis and angiogenesis of gastric cancer cells. BMC Cancer. 2010;10:33.
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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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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DOI: https://doi.org/10.1038/s41388-018-0128-0
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