The chromatin remodelling factor BRG1 is a novel binding partner of the tumor suppressor p16INK4a.
BACKGROUND
CDKN2A/p16INK4a is frequently altered in human cancers and it is the most important melanoma susceptibility gene identified to date. p16INK4a 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 p16INK4a and could help explain its specific association with melanoma predisposition. To identify such functions we conducted a yeast-two-hybrid screen for novel p16INK4a binding partners.


RESULTS
We now report that p16INK4a interacts with the chromatin remodelling factor BRG1. We investigated the cooperative roles of p16INK4a and BRG1 using a panel of cell lines and a melanoma cell model with inducible p16INK4a expression and BRG1 silencing. We found evidence that BRG1 is not required for p16INK4a-induced cell cycle inhibition and propose that the p16INK4a-BRG1 complex regulates BRG1 chromatin remodelling activity. Importantly, we found frequent loss of BRG1 expression in primary and metastatic melanomas, implicating this novel p16INK4a binding partner as an important tumour suppressor in melanoma.


CONCLUSIONS
This data adds to the increasing evidence implicating the SWI/SNF chromatin remodelling complex in tumour development and the association of p16INK4a with chromatin remodelling highlights potentially new functions that may be important in melanoma predisposition and chemoresistance.
Becker
Therese M
TM
Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute and Westmead Hospital, Australia. therese_becker@wmi.usyd.edu.au
Haferkamp
Sebastian
S
Dijkstra
Menno K
MK
Scurr
Lyndee L
LL
Frausto
Monika
M
Diefenbach
Eve
E
Scolyer
Richard A
RA
Reisman
David N
DN
Mann
Graham J
GJ
Kefford
Richard F
RF
Rizos
Helen
H
D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism* / Q000502:physiology; D004265:DNA Helicases / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008545:Melanoma / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D020798:Two-Hybrid System Techniques
D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases