The Ezh2 polycomb group protein drives an aggressive phenotype in melanoma cancer stem cells and is a target of diet derived sulforaphane.
The Ezh2 polycomb group protein drives an aggressive phenotype in melanoma cancer stem cells and is a target of diet derived sulforaphane.
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DOI：
10.1002/mc.22448
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发表时间：
2016-12
影响因子：
4.6
通讯作者：
Eckert RL
中科院分区：
文献类型：
--
作者：
Fisher ML;Adhikary G;Grun D;Kaetzel DM;Eckert RL
黑色素瘤是一种与生存率低相关的转移性癌症。在这里，我们研究了黑色素瘤癌细胞的亚群，显示黑色素瘤癌干细胞（MCS细胞）的特性，包括干细胞标志物的表达升高，作为球状体生存的能力增加，细胞迁移和侵袭增强。我们发现Ezh 2干细胞存活蛋白在MCS细胞中富集，并且Ezh 2敲低或用小分子Ezh 2抑制剂GSK 126或EPZ-6438处理降低了Ezh 2活性。这种减少与MCS细胞球状体形成、迁移和侵袭减少有关。此外，饮食来源的癌症预防剂萝卜硫素（SFN）抑制MCS细胞存活，这与Ezh 2的丧失有关。Ezh 2的强制表达部分逆转了SFN对MCS细胞球体形成、迁移和侵袭的抑制。A375黑色素瘤细胞衍生的MCS细胞在免疫受损小鼠中形成快速生长的肿瘤，并且这些肿瘤的SFN处理减少肿瘤生长，并且这与Ezh 2水平和H3 K27 me 3形成降低、基质金属蛋白酶表达降低、TIMP 3表达增加和细胞凋亡增加相关。这些研究将Ezh 2鉴定为MCS细胞标志物和癌症干细胞预防靶点，并表明SFN通过包括抑制Ezh 2功能的机制来减少黑色素瘤肿瘤形成。
Melanoma is a metastatic cancer associated with poor survival. Here, we study a subpopulation of melanoma cancer cells displaying melanoma cancer stem cell (MCS cells) properties including elevated expression of stem cell markers, increased ability to survive as spheroids, and enhanced cell migration and invasion. We show that the Ezh2 stem cell survival protein is enriched in MCS cells and that Ezh2 knockdown or treatment with small molecule Ezh2 inhibitors, GSK126 or EPZ-6438, reduces Ezh2 activity. This reduction is associated with a reduced MCS cell spheroid formation, migration, and invasion. Moreover, the diet-derived cancer prevention agent, sulforaphane (SFN), suppresses MCS cell survival and this is associated with loss of Ezh2. Forced expression of Ezh2 partially reverses SFN suppression of MCS cell spheroid formation, migration, and invasion. A375 melanoma cell-derived MCS cells form rapidly growing tumors in immune-compromised mice and SFN treatment of these tumors reduces tumor growth and this is associated with reduced Ezh2 level and H3K27me3 formation, reduced matrix metalloproteinase expression, increased TIMP3 expression and increased apoptosis. These studies identify Ezh2 as a MCS cell marker and cancer stem cell prevention target, and suggest that SFN acts to reduce melanoma tumor formation via a mechanism that includes suppression of Ezh2 function.