MCF7 time-series upon RITA treatment.

Targeting oncogene addiction is a promising strategy for anti-cancer therapy. Here, we report a potent inhibition of crucial oncogenes by p53 upon reactivation with small molecule RITA in vitro and in vivo. RITA-activated p53 unleashes transcriptional repression of anti-apoptotic proteins Mcl-1, Bcl-2, MAP4, and survivin, blocks Akt pathway on several levels and downregulates c-Myc, cyclin E and B-catenin. p53 ablates c-Myc expression via several mechanisms at transcriptional and posttranscriptional level. We show that transrepression of oncogenes correlated with higher level of p53 bound to chromatin-bound p53 than transactivation of pro-apoptotic targets. Inhibition of oncogenes by p53 reduces the cells ability to buffer pro-apoptotic signals and elicits robust apoptosis. Our study highlights the role of transcriptional repression for p53-mediated tumor suppression.

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Grinkevich VV, Nikulenkov F, Shi Y, Enge M, Bao W, Maljukova A, Gluch A, Kel A, Sangfelt O, Selivanova G