A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1
A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1
复制标题
新型FLI1外显子环状RNA通过协调调节TET1和DNMT1促进乳腺癌转移
DOI：
10.1186/s13059-018-1594-y
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发表时间：
2018-12-11
期刊：
影响因子：
12.3
通讯作者：
Cui, Jiuwei
中科院分区：
文献类型：
--
作者：
Chen, Naifei;Zhao, Gang;Cui, Jiuwei
Friend白血病病毒整合1（FLI 1）是ETS转录因子家族成员，在血液恶性肿瘤中充当致癌驱动因子，并促进实体瘤中的肿瘤生长。然而，关于这种原癌基因在肿瘤中激活的潜在机制知之甚少。免疫组化染色显示FLI 1在晚期和转移性乳腺癌中异常过表达。使用CRISPR Cas9引导的免疫沉淀分析，我们在FLI 1启动子染色质复合物中鉴定了一种环状RNA，由FLI 1外显子4-2-3组成，称为FECR1.FECR1的过表达增强了MDA-MB 231乳腺癌细胞的侵袭力。值得注意的是，FECR 1利用正反馈机制通过诱导启动子CpG岛中的DNA低甲基化来激活FLI 1。FECR 1与FLI 1启动子顺式结合并募集TET 1，TET 1是一种积极参与DNA去甲基化的去甲基化酶。FECR 1还结合并下调反式DNMT 1，这是一种对维持DNA甲基化至关重要的甲基转移酶。这些数据表明，FECR 1环状RNA作为上游调节因子，通过协调DNA甲基化和去甲基化酶的调节来控制乳腺癌肿瘤生长。因此，FLI 1不仅通过典型的癌蛋白途径驱动肿瘤转移，而且还通过使用由其外显子环状RNA介导的表观遗传机制来驱动肿瘤转移。
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. 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. 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.