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.

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.

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.