Abstract
Abstract Malignant melanoma is an extremely aggressive disease with high metastatic potential. Several studies have shown that the transcription factor E2F1 is overexpressed in melanoma. E2F1 belongs to the family of E2F transcription factors; is more abundant in melanoma cells than in normal melanocytes, which highlights its relevance to melanoma biology. E2F1 participates in a variety of biological processes such as proliferation, apoptosis, development, differentiation, DNA damage and repair, oxidative metabolism, and self-renewal by virtue of its transcriptional activator functions. However, its role in many of these biological processes in melanoma is not yet fully addressed. In this study, we show that E2F1 deficiency increased migration and invasion of melanoma cells, which was associated with increased MYLK at both RNA and protein level. MYLK is a calcium-calmodulin (Ca2+//CaM)-dependent myosin light chain kinase, which phosphorylates Ser-19 of myosin II after activation. This process is implicated in the regulation of smooth muscle contraction. In non-smooth muscle, MYLK is known to be involved in many inflammatory diseases through regulation of tight junction and intestinal epithelial barrier function. MYLK is also involved with proliferation and migration in cancers of the breast, prostate and colon, but its expression and role in melanoma cells is unknown. ML-7, the specific inhibitor for MYLK abrogated the increased migration and invasion due to E2F1 deficiency. Transient knockdown of MYLK also significantly abrogated the increased migration and invasion from E2F1 deficiency. Our results strongly suggest that E2F1 deficiency enhanced migration and invasion through regulating MYLK expression. We also found increased pERK in E2F1 knockdown cells, which suggest that ERK activation may be involved in the up-regulation of MYLK. All of our data taken together suggests that E2F1-mediated inhibition of melanoma cell migration occurs through a complex cross-talk between E2F1-ERK-MYLK and is not through a simple linear relationship between signaling molecules. Supported by R21 CA125719 (RG). Citation Format: Peng Meng, Rita Ghosh. E2F1 deficiency causes increased migration through upregulation of MYLK. [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 4994. doi:10.1158/1538-7445.AM2014-4994
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