Targeting 14-3-3 Epsilon Activates Apoptotic Signaling To Prevent Cutaneous Squamous Cell Carcinoma

More than a million cases of cutaneous squamous cell carcinoma are diagnosed in the USA each year, and its incidence is increasing. Most of these malignancies arise from premalignant lesions, providing an opportunity for intervention before malignant progression. We previously documented how cytoplasmic mislocalization of CDC25A in premalignant and malignant skin cancers confers resistance to apoptotic cell death via a mechanism that depends on its interaction with 14-3-3 epsilon. From these data, we hypothesized that 14-3-3 epsilon overexpression drives skin tumor development and progression, such that targeting 14-3-3 epsilon may be a useful strategy for skin cancer treatment. Like CDC25A, 14-3-3 epsilon was overexpressed and mislocalized to the cytoplasm of both benign and malignant human skin cancer. Skin-targeted deletion of the 14-3-3 epsilon gene reduced skin tumor development by 75% and blocked malignant progression. 14-3-3 epsilon suppressed apoptosis through activation of Akt, leading to inhibition of BCL2 associated agonist of cell death and upregulation of Survivin. Using virtual tetrapeptide libraries, we developed a novel peptide that specifically blocked 14-3-3 epsilon heterodimerization and thereby prevented its interaction with CDC25A. The peptide reduced prosurvival signaling, killed skin cancer cells and reduced skin tumor growth in xenograft. Normal skin keratinocytes were unaffected by inhibition or deletion of 14-3-3 epsilon. Thus, targeting of 14-3-3 epsilon dimerization is a promising strategy for the treatment of premalignant skin lesions.