Abstract
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.
Highlights
Epidermal squamous cell carcinoma is an extremely prevalent disease that is caused by skin exposure to various mutagens including UV irradiation [1]
We recently showed that Large Tumor Suppressor 1 (LATS1), YAP1 and ∆Np63α comprise an important survival cascade in ECS cells [7]
Our studies show that SFN treatment increases YAP1 phosphorylation and degradation, reduces ∆Np63α levels and reduces ECS cell survival, spheroid formation, invasion, migration and tumor formation
Summary
Epidermal squamous cell carcinoma is an extremely prevalent disease that is caused by skin exposure to various mutagens including UV irradiation [1]. It is treated by surgery, but the recurrence rate approaches 10% and the recurring tumors are aggressive and therapy resistant [1]. We recently showed that LATS1, YAP1 and ∆Np63α comprise an important survival cascade in ECS cells [7] Based on these studies, we proposed that suppression of LATS1 (Hippo) signaling leads to enhanced nuclear accumulation of YAP1 which forms a complex with and stabilizes ∆Np63α to enhance ECS cell survival [7]. Reduced LATS1 kinase activity is associated with enhanced cell proliferation [9], and LATS1 activity is often constitutively reduced in cancer cells [9]
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