Abstract 5445: Differential roles of E2F1 in melanoma.

Abstract

Abstract Melanoma, the malignant tumor of melanocytes, accounts for 4% of all skin cancer incidence but approximately 78% of skin cancer related deaths. No current treatment significantly enhances disease-free survival once distant metastases have established. The 5 year survival rate drops dramatically from 99.9% to 9% when melanoma progresses. To facilitate the development of effective treatment strategies, it is imperative that we obtain a better understanding of the biology of melanoma cells as they progress through the various stages of disease. Previous studies have shown that E2F1, a transcription factor, is over-expressed in melanoma cells. Interaction between E2Fs and tumor suppressor, Rb is essential for regulation of cell cycle progression. E2F1 is known to be involved in many other important biological processes, including DNA damage, DNA repair, differentiation, development, autophagy and apoptosis. Involvement of E2F1 in so many diverse functions underscores the importance of this protein under normal and pathologic conditions including melanoma. Previously we have found that primary melanoma cells have high level of E2F1 message and protein, and that the acetylation of E2F1 (active form) is higher in late stage melanoma cells. This led us to propose that E2F1 may function differentially in various stages of melanoma progression. Therefore we generated stable E2F1 knockdown cells in early stage primary and advanced metastatic melanoma cells. Our results show that E2F1 reduction works more effectively to inhibit cell growth in primary melanoma cells. Further, we also found differential effects on apoptosis and invasion in early and late stage melanoma cells. There is increased spontaneous cell death in primary melanoma cells after E2F1 knockdown, while there is increased apoptosis resistance in response to UV or valinomycin. These results taken together suggest that E2F1 has pleotropic effects in melanoma. It can switch between oncogenic or tumor suppressive functions during melanoma progression. A better understanding of the mechanism involved in this switch may allow combining gene therapies with other therapies for improved therapeutics for malignant melanoma. Supported by R21 CA125719 (RG). Citation Format: Peng Meng, Rita Ghosh. Differential roles of E2F1 in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5445. doi:10.1158/1538-7445.AM2013-5445