Nuclear protein pirin negates the cellular senescence barrier against cancer development

Abstract

Pirin (PIR) is a highly conserved protein whose biological role has not yet been fully elucidated. Several studies reported its involvement in cancer progression, proposing a function in apoptosis. We have shown that PIR is primarily expressed in melanocytes and melanoma cells and displays a complex pattern of expression and localization. High levels of PIR protein are found in normal melanocytes whereas low or undetectable levels are present in nevi. Additionally, PIR expression is found in a subset of melanoma cases with increasing levels correlating with tumor progression. Knock-down experiments performed in melanoma cells with high PIR expression have shown a role for PIR in controlling cellular senescence. In this model, PIR ablation results in impairment of cell proliferation, morphological changes characteristic of cellular senescence and expression of senescence markers. Furthermore, oncogene activation and other senescence stimuli induce PIR downregulation. Based on our data, we propose here two alternative models to explain PIR expression pattern in nevi and melanoma and its involvement in the control of senescence. We propose that PIR plays a prominent role in negatively controlling senescence in melanocytic cells and that it could represent a novel marker for melanoma progression and a potential therapeutic target.