Catalytic domain-dependent and -independent transcriptional activities of the tumour suppressor histone H3K27 demethylase UTX/KDM6A in specific cancer types

The histone H3K27 demethylase, UTX/KDM6A, plays a critical role in the early development of vertebrates, and mutations are frequently found in various cancers. Several studies on developmental and cancer biology have focused on preferential transcriptional regulation by UTX independently of its H3K27 demethylase catalytic activity. Here, we analysed gene expression profiles of wild-type (WT) UTX and a catalytic activity-defective mutant in 786-O and HCT116 cells and confirmed that catalytic activity-dependent and -independent regulation contributes to the expression of most of the target genes. Indeed, the catalytic activity-defective mutant indeed suppressed colony formation similar to the WT in our assay system. However, the expression of several genes was significantly dependent on the catalytic activity of UTX in a cell type-specific manner, which could account for the inherent variation in the transcriptional landscape of various cancer types. The promoter/enhancer regions of the catalytic activity-dependent genes identified here were found to be preferentially modified with H3K4me1 and less with H3K27me3 than those of the independent genes. These findings, combined with previous reports, highlight not only the understanding of determinants for the catalytic activity dependency but also the development and application of pharmaceutical agents targeting the H3K27 or H3K4 modifications.