期刊
GENOME BIOLOGY
卷 19, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s13059-018-1594-y
关键词
Circular RNA; FLI1; Breast cancer; DNA methylation; TET1; DNMT1; Tumor
资金
- Research on Chronic Noncommunicable Diseases Prevention and Control of National Ministry of Science and Technology [2016YFC1303804]
- Nation Key Research and Development Program of China [2016YFC13038000]
- Key Project of Chinese Ministry of Education [311015]
- National Natural Science Foundation of China [81672275, 31430021, 81372835, 81670143]
- Jilin Provincial Key Laboratory of Biological Therapy [20170622011JC]
- Provincial Science Fund of Jilin Province Development and Reform Commission [2014 N147, 2017C022]
- Natural Science Foundation of Jilin Province [20150101176JC]
- National Health Development Planning Commission Major Disease Prevention and Control of Science and Technology Plan of Action, Cancer Prevention and Control [ZX-07-C2016004]
- National Key R&D Program of China [2018YFA0106902]
- National Basic Research Program of China (973 Program) [2015CB943303]
- Natural Science Foundation of Jilin Science and Technique [20180101117JC]
- California Institute of Regenerative Medicine (CIRM) grant [RT2-01942]
- Jilin Science and Technique International Collaboration grant [20130413010GH]
- Department of Veterans Affairs [BX002905]
BackgroundFriend leukemia virus integration 1 (FLI1), an ETS transcription factor family member, acts as an oncogenic driver in hematological malignancies and promotes tumor growth in solid tumors. However, little is known about the mechanisms underlying the activation of this proto-oncogene in tumors.ResultsImmunohistochemical staining showed that FLI1 is aberrantly overexpressed in advanced stage and metastatic breast cancers. Using a CRISPR Cas9-guided immunoprecipitation assay, we identify a circular RNA in the FLI1 promoter chromatin complex, consisting of FLI1 exons 4-2-3, referred to as FECR1.Overexpression of FECR1 enhances invasiveness of MDA-MB231 breast cancer cells. Notably, FECR1 utilizes a positive feedback mechanism to activate FLI1 by inducing DNA hypomethylation in CpG islands of the promoter. FECR1 binds to the FLI1 promoter in cis and recruits TET1, a demethylase that is actively involved in DNA demethylation. FECR1 also binds to and downregulates in trans DNMT1, a methyltransferase that is essential for the maintenance of DNA methylation.ConclusionsThese data suggest that FECR1 circular RNA acts as an upstream regulator to control breast cancer tumor growth by coordinating the regulation of DNA methylating and demethylating enzymes. Thus, FLI1 drives tumor metastasis not only through the canonical oncoprotein pathway, but also by using epigenetic mechanisms mediated by its exonic circular RNA.
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