The circACTN4 interacts with FUBP1 to promote tumorigenesis and progression of breast cancer by regulating the expression of proto-oncogene MYC.
The circACTN4 interacts with FUBP1 to promote tumorigenesis and progression of breast cancer by regulating the expression of proto-oncogene MYC.
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DOI：
10.1186/s12943-021-01383-x
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发表时间：
2021-06-11
期刊：
影响因子：
37.3
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Wang X;Xing L;Yang R;Chen H;Wang M;Jiang R;Zhang L;Chen J
最近的研究表明，环状rna （circRNAs）在包括乳腺癌（BC）在内的多种癌症的发生和发展中发挥着重要作用。然而，大多数circrna的潜在功能和BC进展的分子机制仍然难以捉摸。在4对乳腺癌组织和癌旁组织中执行环状RNA芯片。采用qRT-PCR和原位杂交技术检测circACTN4在BC细胞和组织中的表达及预后意义。通过功能获得和功能丧失实验，在体外和体内观察circACTN4对BC细胞生长、侵袭和转移的影响。在机制上，进行了染色质免疫沉淀、荧光素酶报告基因、RNA下拉、质谱、RNA免疫沉淀、荧光原位杂交和共免疫沉淀试验。CircACTN4在乳腺癌组织和细胞中表达显著上调，其表达与BC患者的临床分期及预后不良相关。circACTN4的异位表达在体外和体内显著促进乳腺癌细胞的生长、侵袭和转移。而敲低circACTN4则显示出相反的作用。CircACTN4主要分布在细胞核内。进一步的机制研究证实，circACTN4可竞争性结合远上游元件结合蛋白1 (FUBP1)，阻止FUBP1与FIR结合，从而激活MYC转录，促进乳腺癌的肿瘤进展。此外，我们发现上游转录因子2 （USF2）可能促进circACTN4的生物发生。我们的发现揭示了一个关键机制，即USF2介导的circACTN4可能通过增强MYC的表达，与FUBP1相互作用，促进乳腺癌的发生和发展。CircACTN4可能是诊断和治疗乳腺癌的一个新的潜在靶点。在线版本包含补充材料，可在10.1186/s12943-021-01383-x获得。
Recent studies have revealed that circular RNAs (circRNAs) play significant roles in the occurrence and development of many kinds of cancers including breast cancer (BC). However, the potential functions of most circRNAs and the molecular mechanisms underlying progression of BC remain elusive. Here, Circular RNA microarray was executed in 4 pairs of breast cancer tissues and para-cancer tissues. The expression and prognostic significance of circACTN4 in BC cells and tissues were determined by qRT-PCR and in situ hybridization. Gain-and loss-of-function experiments were implemented to observe the impacts of circACTN4 on the growth, invasion, and metastasis of BC cells in vitro and in vivo. Mechanistically, chromatin immunoprecipitation, luciferase reporter, RNA pulldown, mass spectrum, RNA immunoprecipitation, fluorescence in situ hybridization and co-immunoprecipitation assays were executed. CircACTN4 was significantly upregulated in breast cancer tissues and cells, its expression was correlated with clinical stage and poor prognosis of patients with BC. Ectopic expression of circACTN4 strikingly facilitated the growth, invasion, and metastasis of breast cancer cells in vitro and in vivo. Whereas knockdown of circACTN4 revealed opposite roles. CircACTN4 was mainly distributed in the nucleus. Further mechanistic research proved that circACTN4 could competitively bind to far upstream element binding protein 1 (FUBP1) to prevent the combination between FUBP1 and FIR, thereby activating MYC transcription and facilitating tumor progression of breast cancer. Furthermore, we found that upstream transcription factor 2 (USF2) might promote the biogenesis of circACTN4. Our findings uncover a pivotal mechanism that circACTN4 mediated by USF2 might interact with FUBP1 to promote the occurrence and development of breast cancer via enhancing the expression of MYC. CircACTN4 could be a novel potential target for diagnosis and treatment of breast cancer. The online version contains supplementary material available at 10.1186/s12943-021-01383-x.
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