Fisher Matthew L, Ciavattone Nicholas, Grun Daniel, Adhikary Gautam, Eckert Richard L
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Oncotarget. 2017 Aug 27;8(43):73407-73418. doi: 10.18632/oncotarget.20562. eCollection 2017 Sep 26.
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.
表皮鳞状细胞癌（SCC）是最常见的癌症之一。SCC可通过手术切除进行治疗，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信号转导转录衔接蛋白YAP1与关键的表皮干细胞存活蛋白∆Np63α形成复合物，以驱动表皮癌干细胞的存活。在本研究中，我们证明YAP1和∆Np63α是萝卜硫素预防癌症的重要靶点。我们发现萝卜硫素处理可增加YAP1的磷酸化和蛋白水解降解。YAP1的缺失与∆Np63α水平的降低以及表皮癌干细胞（ECS）存活、球体形成、侵袭和迁移能力的降低有关。YAP1和∆Np63α的缺失由蛋白酶体介导，并且可通过乳胞素处理来抑制。敲低YAP1或∆Np63α可重现对萝卜硫素的反应，而恢复YAP1或∆Np63α则可拮抗萝卜硫素的作用。萝卜硫素可抑制ECS细胞肿瘤形成，这与YAP1和∆Np63α水平的降低有关。这些研究表明，YAP1和∆Np63α可能是萝卜硫素预防表皮鳞状细胞癌的重要靶点。
