We report that JMJD3, a H3K27me3 specific demethylase, is induced during differentiation of patient-derived glioblastoma stem cells (GSCs), where it promotes a differentiation-like phenotype via a chromatin dependent (INK4A/ARF locus activation) and chromatin independent (direct p53 protein stabilization) mechanism resulting in a p53-mediated cell cycle arrest and differentiation. The gene discussed is CDKN2A; the disease is glioblastoma.