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.

中文翻译：

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circACTN4与FUBP1相互作用通过调节原癌基因MYC的表达促进乳腺癌的发生和进展

最近的研究表明，环状RNA（circRNA）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。在这里，环状 RNA 微阵列在 4 对乳腺癌组织和癌旁组织中进行。通过qRT-PCR和原位杂交确定了circACTN4在BC细胞和组织中的表达和预后意义。实施增益和功能丧失实验，观察circACTN4对体外和体内BC细胞生长、侵袭和转移的影响。机制上，染色质免疫沉淀，荧光素酶报告基因，RNA pulldown，质谱，RNA 免疫沉淀，进行荧光原位杂交和免疫共沉淀测定。CircACTN4在乳腺癌组织和细胞中显着上调，其表达与BC患者的临床分期和预后不良有关。circACTN4 的异位表达显着促进了体外和体内乳腺癌细胞的生长、侵袭和转移。而 circACTN4 的敲除则显示出相反的作用。CircACTN4主要分布在细胞核中。进一步的机理研究证明，circACTN4可以与远上游元件结合蛋白1（FUBP1）竞争性结合，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 的生物合成。我们的研究结果揭示了一个关键机制，即 USF2 介导的 circACTN4 可能与 FUBP1 相互作用，通过增强 MYC 的表达来促进乳腺癌的发生和发展。CircACTN4 可能是乳腺癌诊断和治疗的一个新的潜在靶点。