Sulforaphane reduces YAP/∆Np63α signaling to reduce cancer stem cell survival and tumor formation.
Sulforaphane reduces YAP/∆Np63α signaling to reduce cancer stem cell survival and tumor formation.
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DOI：
10.18632/oncotarget.20562
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发表时间：
2017-09-26
期刊：
影响因子：
--
通讯作者：
Eckert RL
中科院分区：
文献类型：
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作者：
Fisher ML;Ciavattone N;Grun D;Adhikary G;Eckert RL
表皮鳞状细胞癌（SCC）是最常见的癌症之一。SCC可以通过手术切除治疗，但治疗抵抗性疾病的复发是一个主要问题。我们最近发现，Hippo信号转录接头蛋白YAP1和表皮干细胞存活关键蛋白∆Np63α形成一个复合体，驱动表皮癌干细胞存活。在本研究中，我们证实了YAP1和∆Np63α是萝卜硫素重要的防癌靶点。我们发现萝卜硫素处理增加了YAP1磷酸化和蛋白水解降解。YAP1的缺失与∆Np63α水平的降低以及ECS细胞存活、球体形成、侵袭和迁移的减少有关。YAP1和∆Np63α的丢失是由蛋白酶体介导的，并可通过乳酸蛋白酶抑制。YAP1或∆Np63α基因敲低可复制对萝卜硫素的反应，而YAP1或∆Np63α基因的恢复可拮抗萝卜硫素的作用。萝卜硫素抑制ECS细胞肿瘤形成，这与YAP1和∆Np63α水平降低有关。这些研究提示YAP1和∆Np63α可能是表皮鳞状细胞癌中重要的萝卜硫素防癌靶点。
Epidermal squamous cell carcinoma (SCC) is among the most common cancers. SCC can be treated by surgical excision, but recurrence of therapy-resistant disease is a major problem. We recently showed that YAP1, the Hippo signaling transcription adaptor protein, and ∆Np63α, a key epidermal stem cell survival protein, form a complex to drive epidermal cancer stem cell survival. In the present study, we demonstrate that YAP1 and ∆Np63α are important sulforaphane cancer prevention targets. We show that sulforaphane treatment increases YAP1 phosphorylation and proteolytic degradation. The loss of YAP1 is associated with a reduction in ∆Np63α level and a reduction in ECS cell survival, spheroid formation, invasion and migration. Loss of YAP1 and ∆Np63α is mediated by the proteasome and can be inhibited by lactacystin treatment. YAP1 or ∆Np63α knockdown replicates the responses to sulforaphane, and restoration of YAP1 or ∆Np63α antagonizes sulforaphane action. Sulforaphane suppresses ECS cell tumor formation and this is associated with reduced levels of YAP1 and ∆Np63α. These studies suggest that YAP1 and ∆Np63α may be important sulforaphane cancer preventive targets in epidermal squamous cell carcinoma.