c-JUN prevents methylation of p16INK4a (and Cdk6): the villain turned bodyguard

Karoline Kollmann 1 , Gerwin Heller 2 , Veronika Sexl 1 1 Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria 2 Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer, Medical University of Vienna (MUV), Vienna, Austria Keywords: AP-1, CDK6, p16, leukemia Received: May 27, 2011; Accepted: May 28, 2011; Published: May 28, 2011; Correspondence: Karoline Kollmann, e-mail: // // Abstract A novel way by which the AP-1 factor c-JUN interferes with tumorigenesis has recently been elucidated [1]. In a model of murine leukemia, c-JUN prevents the epigenetic silencing of the cell cycle kinase CDK6. In the absence of c-JUN, CDK6 is down-regulated and the 5’region of the gene is methylated. Down-regulation of CDK6 results in significantly delayed leukemia formation. Here we show that c-JUN is also involved in protecting the promoter region of the tumor suppressor p16 INK4a , which is consistently methylated over time in c-JUN deficient cells. In cells expressing c-JUN, p16 INK4a promoter methylation is a less frequent event. Our study unravels a novel mechanism by which the AP-1 factor c-JUN acts as a “bodyguard”, and preventing methylation of a distinct set of genes after oncogenic transformation.