Characterisation of the EZH2 regulated transcriptome in de novo transformed cells (RNA-Seq)

Epigenetic regulators are often hijacked by cancer cells to sustain and enhance their malignant phenotypes. Co-opted proteins are typically not mutated and their intrinsic properties remain unaltered. How cancer 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. In this study, we show that oncogenic signalling induces redistribution of EZH2 across the genome, which in turn misregulates key homeotic genes and corrupts the identity of neural cells. Characterisation of EZH2 direct targets in de novo transformed cells 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 key regulator of neurogenesis in the forebrain and negative regulator of neural stem cell proliferation. Our results suggest that by redistributing EZH2 across the genome, cancer cells subvert developmental transcriptional programs that specify normal cell identity and remove physiological breaks that normally restrain cell proliferation. The transcriptome of cells at different stages of de novo neoplastic transformation treated with an EZH2 inhibitor or DMSO control was characterised by total RNA-seq, in triplicate, using an Illumina Hiseq 4000.