一种新型的 FLI1 外显子环状 RNA 通过协调调控 TET1 和 DNMT1 促进乳腺癌转移。
A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1.
机构信息
Stem Cell and Cancer Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 133021, Jilin, China.
Department of Breast Cancer Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 133021, Jilin, China.
出版信息
Genome Biol. 2018 Dec 11;19(1):218. doi: 10.1186/s13059-018-1594-y.
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.
背景
Friend 白血病病毒整合 1（FLI1）是 ETS 转录因子家族的一员，作为血液系统恶性肿瘤的致癌驱动因子，并促进实体肿瘤的肿瘤生长。然而，人们对这种原癌基因在肿瘤中激活的机制知之甚少。
结果
免疫组织化学染色显示，FLI1 在晚期和转移性乳腺癌中异常过表达。使用 CRISPR Cas9 引导的免疫沉淀测定法，我们在 FLI1 启动子染色质复合物中鉴定出一种由 FLI1 外显子 4-2-3 组成的环状 RNA，称为 FECR1。FECR1 的过表达增强了 MDA-MB231 乳腺癌细胞的侵袭性。值得注意的是，FECR1 通过诱导启动子 CpG 岛中的 DNA 低甲基化，利用正反馈机制激活 FLI1。FECR1 在顺式结合 FLI1 启动子并招募 TET1，TET1 是一种积极参与 DNA 去甲基化的去甲基酶。FECR1 还结合并下调反式 DNMT1，DNMT1 是维持 DNA 甲基化所必需的甲基转移酶。
结论
这些数据表明，FECR1 环状 RNA 作为一种上游调节剂，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的生长。因此，FLI1 不仅通过经典的癌蛋白途径，而且通过其外显子环状 RNA 介导的表观遗传机制驱动肿瘤转移。
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