The chromatin remodelling factor BRG1 is a novel binding partner of the tumor suppressor p16(INK4a)

BACKGROUND: CDKN2A/p16(INK4a )is frequently altered in human cancers and it is the most important melanoma susceptibility gene identified to date. p16(INK4a )inhibits pRb phosphorylation and induces cell cycle arrest, which is considered its main tumour suppressor function. Nevertheless, additional activities may contribute to the tumour suppressor role of p16(INK4a )and could help explain its specific association with melanoma predisposition. To identify such functions we conducted a yeast-two-hybrid screen for novel p16(INK4a )binding partners. RESULTS: We now report that p16(INK4a )interacts with the chromatin remodelling factor BRG1. We investigated the cooperative roles of p16(INK4a )and BRG1 using a panel of cell lines and a melanoma cell model with inducible p16(INK4a )expression and BRG1 silencing. We found evidence that BRG1 is not required for p16(INK4a)-induced cell cycle inhibition and propose that the p16(INK4a)-BRG1 complex regulates BRG1 chromatin remodelling activity. Importantly, we found frequent loss of BRG1 expression in primary and metastatic melanomas, implicating this novel p16(INK4a )binding partner as an important tumour suppressor in melanoma. CONCLUSION: This data adds to the increasing evidence implicating the SWI/SNF chromatin remodelling complex in tumour development and the association of p16(INK4a )with chromatin remodelling highlights potentially new functions that may be important in melanoma predisposition and chemoresistance.