Characterisation of EZH2 targets in de novo transformed cells, combined with analysis of glioma patient datasets and cell lines, reveals that acquisition of tumorigenic potential is accompanied by a transcriptional switch involving de‐repression of spinal cord‐specifying HOX genes and concomitant silencing of the empty spiracles homologue EMX2, a critical regulator of neurogenesis in the forebrain. This evidence concerns the gene EZH2 and central nervous system cancer.