Abstract:
Epigenetic perturbations are key events in the initiation and progression of cancer. One such epigenetic modification, the trimethylation of lysine 27 of histone 3 (H3K27me3), occurs at gene promoters and is associated with transcriptional silencing. H3K27me3 is deposited on chromatin by an epigenetic complex termed Polycomb Repressive Complex 2 (PRC2). Lysine demethylase 6A (KDM6A) is a histone demethylase which acts in opposition to PRC2, removing methyl groups from H3K27. KDM6A is mutated in many cancers and this event is thought to amplify PRC2 activity, resulting in aberrant accumulation of H3K27me3 during tumourigenesis. Previous research indicated that treating KDM6A-deficient cancer cell lines with PRC2 inhibitors could decrease H3K27me3 levels and de-repress genes linked to PRC2 silencing, potentially indicating a therapeutic response. Studies also suggested cancers with mutations in isocitrate dehydrogenase 1 (IDH1) display defective KDM6A catalytic activity and this feature may similarly cause sensitivity to PRC2 inhibition. In this project we investigated whether KDM6A-deficient cancer cells (either KDM6A mutant or IDH1 mutant) display increased sensitivity to PRC2 inhibitors.....
