FMNL1 mediates nasopharyngeal carcinoma cell aggressiveness by epigenetically upregulating MTA1
FMNL1 mediates nasopharyngeal carcinoma cell aggressiveness by epigenetically upregulating MTA1
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FMNL1通过表观遗传上调MTA1介导鼻咽癌细胞侵袭性
DOI：
10.1038/s41388-018-0351-8
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发表时间：
2018-11-29
期刊：
影响因子：
8
通讯作者：
Xie, Dan
中科院分区：
文献类型：
--
作者：
Chen, Wen-Hui;Cai, Mu-Yan;Xie, Dan
已有研究表明，FMNL1在多种血液系统恶性肿瘤的发病过程中起重要作用。在这项研究中，我们进行了一系列的体内和体外实验，以阐明FMNL1的生物学功能及其在人鼻咽癌发病机制中的作用。在此，我们报告FMNL1在鼻咽癌中的高表达与侵袭性疾病和/或患者生存不良呈正相关。FMNL1在鼻咽癌细胞中的异位过表达显著促进了细胞内翻足的形成、上皮-间充质转化(EMT)和侵袭能力，而FMNL1的缺失则有效地抑制了鼻咽癌细胞内翻足的形成、EMT和侵袭/转移能力。我们进一步证明，FMNL1可以通过增加一个关键的下游靶点，转移相关蛋白1(MTA1)基因来增强鼻咽癌细胞的侵袭力。重要的是，FMNL1在鼻咽癌细胞中的异位过表达显著提高了HDAC1与胞浆中Profilin2的结合，并抑制了HDAC1在MTA1启动子上的浓缩，从而导致MTA1转录和表达的增加。此外，除了FMNL1基因的扩增外，NPC中miR-16水平的降低也是上调FMNL1表达的另一个重要机制。这些结果为FMNL1的高表达提供了第一线证据，FMNL1是由于miR-16和/或MTA1扩增减少而导致的，通过上调MTA1在鼻咽癌的发生和侵袭过程中具有潜在的致癌作用，FMNL1可能成为鼻咽癌新的预后生物标志物和治疗靶点。
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.