Epigenetic regulators are often hijacked by cancer cells to sustain
malignant phenotypes. How cells repurpose key regulators of cell
identity as tumour-promoting factors is unclear. The antithetic
role of the Polycomb component EZH2 in normal brain and glioma
provides a paradigm to dissect how wild-type chromatin modifiers
gain a pathological function in cancer. Here, we show that oncogenic signalling induces redistribution of EZH2 across the genome,
and through misregulation of homeotic genes corrupts the identity
of neural cells. 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. Maintenance of tumorigenic potential by
glioblastoma cells requires EMX2 repression, since forced EMX2
expression prevents tumour formation. Thus, by redistributing
EZH2 across the genome, cancer cells subvert developmental transcriptional programmes that specify normal cell identity and
remove physiological breaks that restrain cell proliferation