It has been suggested that formin-like protein 1 (FMNL1) plays an important role in the pathogenic process of several hematopoietic malignancies. In this study, we performed a series of in vivo and in vitro assays to elucidate the biological functions of FMNL1 and underlying mechanisms in human nasopharyngeal carcinoma (NPC) pathogenesis. Herein, we report that high expression of FMNL1 in NPC is positively associated with an aggressive disease and/or poor patient survival. Ectopic overexpression of FMNL1 in NPC cells substantially promoted cell invadopodia formation, epithelial-mesenchymal transition (EMT) and invasiveness, whereas depletion of FMNL1 potently suppressed NPC cells invadopodia formation, EMT, and invasive/metastatic capacities. We further show that FMNL1 could enhance NPC cell aggressiveness by increasing a key downstream target, the metastasis-associated protein 1 (MTA1) gene. Importantly, ectopic overexpression of FMNL1 in NPC cells markedly improved the binding of HDAC1 with Profilin2 in the cytoplasm and suppressed the enrichment of HDAC1 on the promoter of MTA1 and thereby, leading to an increased MTA1 transcription and expression. Furthermore, in addition to the amplification of FMNL1 gene, decreased level of miR-16 in NPCs is another critical mechanism to upregulate FMNL1 expression. These results, collectively, provide first-line of evidences that high expression of FMNL1, resulted from decreased miR-16 and/or MTA1 amplification, has a potent oncogenic role to drive the development and aggressive process of NPC by upregulating MTA1, and FMNL1 might be employed as a new prognostic biomarker and therapeutic target for human NPC.

中文翻译：

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FMNL1 通过表观遗传上调 MTA1 介导鼻咽癌细胞的侵袭性。


研究表明，福尔明样蛋白1（FMNL1）在多种造血系统恶性肿瘤的发病过程中发挥着重要作用。在本研究中，我们进行了一系列体内和体外测定，以阐明 FMNL1 的生物学功能以及人鼻咽癌 (NPC) 发病机制中的潜在机制。在此，我们报告 FMNL1 在 NPC 中的高表达与侵袭性疾病和/或患者生存率低呈正相关。 NPC细胞中FMNL1的异位过度表达显着促进细胞侵袭伪足形成、上皮间质转化（EMT）和侵袭能力，而FMNL1的耗竭则有效抑制NPC细胞侵袭伪足形成、EMT和侵袭/转移能力。我们进一步表明，FMNL1 可以通过增加关键的下游靶标——转移相关蛋白 1 (MTA1) 基因来增强鼻咽癌细胞的侵袭性。重要的是，NPC细胞中FMNL1的异位过度表达显着改善了细胞质中HDAC1与Profilin2的结合，并抑制了HDAC1在MTA1启动子上的富集，从而导致MTA1转录和表达增加。此外，除了FMNL1基因的扩增外，NPC中miR-16水平的降低是上调FMNL1表达的另一个关键机制。这些结果共同提供了第一线证据，证明 FMNL1 的高表达是由于 miR-16 和/或 MTA1 扩增减少而导致的，具有潜在的致癌作用，可以通过上调 MTA1 来驱动 NPC 的发展和侵袭过程，并且 FMNL1 可能可作为人类鼻咽癌新的预后生物标志物和治疗靶点。