Downregulation of SLC27A6 by DNA Hypermethylation Promotes Proliferation but Suppresses Metastasis of Nasopharyngeal Carcinoma Through Modulating Lipid Metabolism.
Downregulation of SLC27A6 by DNA Hypermethylation Promotes Proliferation but Suppresses Metastasis of Nasopharyngeal Carcinoma Through Modulating Lipid Metabolism.
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DNA 高甲基化下调 SLC27A6 通过调节脂质代谢促进鼻咽癌增殖并抑制转移
DOI：
10.3389/fonc.2021.780410
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发表时间：
2021
影响因子：
4.7
通讯作者：
Zhao W
中科院分区：
文献类型：
--
作者：
Zhong X;Yang Y;Li B;Liang P;Huang Y;Zheng Q;Wang Y;Xiao X;Mo Y;Zhang Z;Zhou X;Huang G;Zhao W
脂质是肿瘤细胞的组成部分和重要的能量来源，有助于肿瘤细胞的恶性行为。最近的研究表明，脂滴（LDs）的积累与鼻咽癌（NPC）的进展有关。溶质载体家族27成员6 （SLC27A6）介导长链脂肪酸（LCFA）的细胞摄取，这是一种必要的脂质成分。然而，SLC27A6在NPC中的功能尚不清楚。在这里，我们发现与正常鼻咽上皮（NNE）相比，鼻咽癌组织中SLC27A6 mRNA显著减少。SLC27A6启动子甲基化率在鼻咽癌组织中高于非癌组织。去甲基化试剂5-aza-2′-脱氧胞苷（5-aza-dC）显著恢复了SLC27A6 mRNA的表达，表明该基因在鼻鼻癌中由于DNA启动子超甲基化而下调。此外，SLC27A6在鼻咽癌细胞系中的过表达水平可显著抑制细胞增殖、体外克隆性和体内肿瘤发生。另一方面，SLC27A6的高表达促进了鼻咽癌细胞的迁移和侵袭。特别是，SLC27A6的重新表达促进了异种移植物肿瘤的上皮-间质转化（EMT）信号。此外，我们观察到SLC27A6增加了鼻咽癌细胞内甘油三酯（TG）和总胆固醇（T-CHO）的数量，有助于脂质生物合成和增加转移潜力。值得注意的是，SLC27A6 mRNA水平与癌症干细胞（CSC）标志物CD24和CD44呈正相关。综上所述，DNA启动子超甲基化下调SLC27A6的表达。此外，SLC27A6的重新表达抑制了鼻咽癌细胞的生长能力，但增强了CSC标志物。我们的研究结果揭示了SLC27A6在NPC中的双重作用，并为脂质代谢和CSC维持之间的联系提供了新的思路。
Lipid is the building block and an important source of energy, contributing to the malignant behavior of tumor cells. Recent studies suggested that lipid droplets (LDs) accumulations were associated with nasopharyngeal carcinoma (NPC) progression. Solute carrier family 27 member 6 (SLC27A6) mediates the cellular uptake of long-chain fatty acid (LCFA), a necessary lipid component. However, the functions of SLC27A6 in NPC remain unknown. Here, we found a significant reduction of SLC27A6 mRNA in NPC tissues compared with normal nasopharyngeal epithelia (NNE). The promoter methylation ratio of SLC27A6 was greater in NPC than in non-cancerous tissues. The demethylation reagent 5-aza-2’-deoxycytidine (5-aza-dC) remarkably restored the mRNA expression of SLC27A6, suggesting that this gene was downregulated in NPC owing to DNA promoter hypermethylation. Furthermore, SLC27A6 overexpression level in NPC cell lines led to significant suppression of cell proliferation, clonogenicity in vitro, and tumorigenesis in vivo. Higher SLC27A6 expression, on the other hand, promoted NPC cell migration and invasion. In particular, re-expression of SLC27A6 faciliated epithelial-mesenchymal transition (EMT) signals in xenograft tumors. Furthermore, we observed that SLC27A6 enhanced the intracellular amount of triglyceride (TG) and total cholesterol (T-CHO) in NPC cells, contributing to lipid biosynthesis and increasing metastatic potential. Notably, the mRNA level of SLC27A6 was positively correlated with cancer stem cell (CSC) markers, CD24 and CD44. In summary, DNA promoter hypermethylation downregulated the expression of SLC27A6. Furthermore, re-expression of SLC27A6 inhibited the growth capacity of NPC cells but strengthened the CSC markers. Our findings revealed the dual role of SLC27A6 in NPC and shed novel light on the link between lipid metabolism and CSC maintenance.
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DOI：
10.1002/path.5130
发表时间：
2018-10
期刊：
The Journal of pathology
影响因子：
--
作者：
Lo AK;Lung RW;Dawson CW;Young LS;Ko CW;Yeung WW;Kang W;To KF;Lo KW
通讯作者：
Lo KW
影响因子：
4.2
作者：
Hao, Qiwei;Li, Tao;Geng, Zhimin
通讯作者：
Geng, Zhimin
DOI：
10.1007/s00005-016-0409-7
发表时间：
2017-04-01
影响因子：
3.2
作者：
Koennecke, Michael;Burmeister, Maike;Wollenberg, Barbara
通讯作者：
Wollenberg, Barbara
CDH4作为一种新型推定肿瘤抑制基因，在鼻咽癌中通过启动子高甲基化而被表观遗传沉默
影响因子：
9.7
作者：
Du, Chunping;Huang, Tingting;Zhang, Zhe
通讯作者：
Zhang, Zhe
影响因子：
6.4
作者：
Li, H. M.;Man, C.;Tsao, S. W.
通讯作者：
Tsao, S. W.