Seminar

Regulation of SNAIL-1 by PARP-1 in metastatic melanoma

Javier Oliver Pozo, PhD

Snail1 is a master regulator of the epithelial-mesenchymal transition (EMT) and has been implicated in key tumour biological processes such as invasion and metastasis. In this study we have characterised a novel regulatory mechanism controlling Snail1 protein expression through poly(ADP-ribosyl)ation. PARP-1 knockdown or its inhibition down-regulates the expression of Snail11. The effect is not limited to repression of Snail1 transcription but also to down-regulated Snail1 protein stability. PARP-1 (but not PARP-2) polyADP-ribosylates Snail1 both in vivo and in vitro and interacts with Snail1, an association that is sensitive to PARP inhibitors. Therefore, this study reveals a new regulatory mechanism of Snail1 activation through poly(ADP-ribosyl)ation with potential antimetastasic effect. In a model of metastatic melanoma, we show that PARP inhibition, is able to countertact metastasis of melanoma cells to lung. Treatment of mice implanted with metastatic melanoma cells increased E-cadherin expression and reduced SNAIL, angiogenesis rate and their invasive potential and mice treated with the PARP inhibitor DPQ had a smaller area of metastasis per lung. These results suggest that inhibition of PARP through its ability to interfere with key metastasis-promoting processes, could suppress invasion and colonization of distant organs by aggressive metastatic cells.