Abstract
Abstract
Non-melanoma skin cancer, the most common cancer in the United States, frequently results from chronic exposure to ultraviolet (UV) irradiation. UV-induced DNA damage activates cell cycle arrest checkpoints through degradation of the cyclin-dependent kinase activators, the Cell Division Cycle 25 (CDC25) phosphatases, which are over-expressed and, thus, deregulate cell cycle control in many human cancers. To investigate a role for CDC25 in skin cancer, CDC25 levels were examined in both UV-induced mouse tumors and human skin cancer. CDC25A and CDC25C protein and transcripts were increased in benign and malignant skin tumors from UV-exposed v-rasHa transgenic Tg.AC mice. CDC25B protein but not transcripts was increased in mouse skin tumors compared to normal skin. Similarly, CDC25A and CDC25C but not CDC25B were elevated in human squamous cell carcinoma (SCC) and in the premalignant precursors actinic keratosis and Bowen's disease when compared to skin. While CDC25A was localized primarily to nuclei in normal epidermis, both the premalignant precursors and SCC exhibited strong cytoplasmic CDC25A localization. To determine whether increased CDC25A stimulates proliferation in skin SCC, CDC25A levels were modulated by siRNA-targeting or forced expression in cultured SCC cells, but no difference in proliferation resulted. Because cytoplasmic CDC25A can bind to the apoptotic regulator 14-3-3, we hypothesized that the increase in cytoplasmic CDC25A may suppress apoptosis. Forced over-expression of CDC25A in SCC cells suppressed cell death, whereas CDC25A silencing increased apoptotic cell death. Phosphorylation of CDC25A at serine178, a docking site for 14-3-3 proteins, was elevated in the cytoplasmic compartment of SCCs, and cytoplasmic 14-3-3ϵ was increased in cutaneous SCC.Mutation of the nuclear export sequence on CDC25A relocalized both CDC25A and 14-3-3ϵ to the nucleus, while mutation of 14-3-3 binding sites on CDC25A led to a decrease in 14-3-3ϵ levels. Furthermore, silencing of 14-3-3ϵ increased cell death by 60%. Taken together, these data suggest that increased cytoplasmic CDC25A in cutaneous SCC may suppress apoptotic cell death through its interaction with 14-3-3ϵ.
Citation Format: Jenan Almatouq, Kristen Ho, Laura A. Hansen. Increased cytoplasmic CDC25A phosphatase in cutaneous squamous cell carcinoma leads to 14-3-3 relocalization and suppression of apoptosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1310. doi:10.1158/1538-7445.AM2014-1310