LNMAT1 Promotes Invasion-Metastasis Cascade in Malignant Melanoma by Epigenetically Suppressing CADM1 Expression
LNMAT1 Promotes Invasion-Metastasis Cascade in Malignant Melanoma by Epigenetically Suppressing CADM1 Expression
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LNMAT1 通过表观遗传学抑制 CADM1 表达促进恶性黑色素瘤的侵袭转移级联反应
DOI：
10.3389/fonc.2019.00569
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发表时间：
2019-07-03
影响因子：
4.7
通讯作者：
Wang, Lijuan
中科院分区：
文献类型：
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作者：
Mou, Kuanhou;Zhang, Xiang;Wang, Lijuan
恶性黑色素瘤（malignant melanoma，MM）的侵袭-转移级联反应是影响患者生存和预后的重要因素之一。淋巴结转移相关长链非编码RNA转录本1（LNMAT 1）是多种肿瘤淋巴结转移的关键调控因子，但LNMAT 1在MM侵袭转移级联反应中的作用及机制尚不清楚。在本研究中，我们的目的是研究LNMAT 1在MM中的表达和功能。在这里，我们发现LNMAT 1在MM组织和细胞中上调，并且其表达水平在伴有淋巴结转移的MM患者和转移性MM细胞中进一步增强。使用功能丧失测定，我们发现LNMAT 1在体外和体内促进MM中的细胞迁移和侵袭以及肺转移。此外，我们发现，细胞粘附分子1（CADM 1），在MM中建立的肿瘤抑制因子，是LNMAT 1的下游靶点。在机制上，LNMAT 1通过将EZH 2（组蛋白H3在赖氨酸27（H3 K27 me 3）处的三甲基化的关键调节剂）募集到CADM 1启动子来表观遗传地抑制CADM 1表达，从而导致CADM 1的转录抑制。最后，拯救测定表明，LNMAT 1通过抑制CADM 1表达促进MM的细胞迁移和侵袭。我们的研究结果阐明了MM中LNMAT 1介导的侵袭-转移级联反应的新机制，并表明LNMAT 1可能是MM的新治疗靶点和预后预测因子。
The invasion-metastasis cascade is one of the most important factors relating to poor survival and prognosis of malignant melanoma (MM) patients. Long non-coding RNA lymph node metastasis associated transcript 1 (LNMAT1) is a key regulator in lymph node metastasis of multiple cancer types, but the roles and underlying mechanisms of LNMAT1 in the invasion-metastasis cascade of MM remain unclear. In the present study, we aimed to investigate the expression and function of LNMAT1 in MM. Here, we found that LNMAT1 was upregulated in MM tissues and cells, and its expression levels were further enhanced in MM patients with lymph node metastasis and metastatic MM cells. Using loss-of-function assays, we found that LNMAT1 promoted cell migration and invasion and lung metastasis in MM in vitro and in vivo. Moreover, we found that cell adhesion molecule 1 (CADM1), the established tumor suppressor in MM, was the downstream target of LNMAT1. Mechanistically, LNMAT1 epigenetically suppressed CADM1 expression by recruiting EZH2, the key regulator of trimethylation of histone H3 at lysine 27 (H3K27me3), to the CADM1 promoter, resulting in transcriptional inhibition of CADM1. Lastly, rescue assays demonstrated that LNMAT1 promoted cell migration and invasion of MM by suppressing CADM1 expression. Our findings elucidate a new mechanism for LNMAT1-mediated invasion-metastasis cascade in MM and suggest that LNMAT1 may be a new therapeutic target and prognostic predictor for MM.