A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1

Genome Biology

Gang Zhao¹  Hongmei Yin²  Andrew R. Hoffman³  Shilin Zhang⁴  Naifei Chen⁴  Xu Yan⁴  Wei Song⁴  Xueli Li⁴  Lei Zhou⁴  Jiuwei Cui⁴  Zheng Lv⁴  Lingyu Li⁴  Wei Li⁴  Lin Jia⁴  Zhonghua Du⁴  Ji-Fan Hu⁴ 

[1] Department of Breast Cancer Surgery, The First Hospital of Jilin University;Department of General Internal Medicine, The First Hospital of Jilin University;Stanford University Medical School, Palo Alto Veterans Institute for Research;Stem Cell and Cancer Center, The First Hospital of Jilin University;

关键词: Circular RNA;    FLI1;    Breast cancer;    DNA methylation;    TET1;    DNMT1;   

DOI  :  10.1186/s13059-018-1594-y

来源: DOAJ

【 摘 要 】

Abstract Background Friend 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. Results Immunohistochemical 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. Conclusions These 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.

【 授权许可】

Unknown