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.

Hypoxia-inducible factor-1α and poly [ADP ribose] polymerase 1 cooperatively regulate Notch3 expression under hypoxia via a noncanonical mechanism.

Upregulation of Notch3 expression has been reported in many cancers and is considered a marker for poor prognosis. Hypoxia is a driving factor of the Notch3 signaling pathway; however, the induction mechanism and role of hypoxia-inducible factor-1α (HIF-1α) in the Notch3 response are still unclear. In this study, we found that HIF-1α and poly [ADP-ribose] polymerase 1 (PARP-1) regulate Notch3 induction under hypoxia via a noncanonical mechanism.

A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition.

UTX/KDM6A encodes a major histone H3 lysine 27 (H3K27) demethylase, and is frequently mutated in various types of human cancers. Although UTX appears to play a crucial role in oncogenesis, the mechanisms involved are still largely unknown. Here we show that a specific pharmacological inhibitor of H3K27 demethylases, GSK-J4, induces the expression of transcription activating factor 4 (ATF4) protein as well as the ATF4 target genes (e.

Cancer-derived UTX TPR mutations G137V and D336G impair interaction with MLL3/4 complexes and affect UTX subcellular localization.

The ubiquitously transcribed tetratricopeptide repeat on X chromosome (UTX) is a major histone H3 lysine 27 (H3K27) demethylase and the mixed-lineage leukemia (MLL) proteins are the H3K4 methyltransferases. UTX is one of the major components of MLL3- and MLL4-containing (MlLL3/4) complexes and likely has functions within the complexes. Although UTX is frequently mutated in various types of cancer and is thought to play a crucial role as a tumor suppressor, the importance of UTX interaction with MLL3/4 complexes in cancer formation is poorly understood.

Hypoxia Regulates MicroRNA Expression in the Human Carotid Body.

How hypoxia regulates gene expression in the human carotid body (CB) remains poorly understood. While limited information on transcriptional regulation in animal CBs is available, the impact of important post-transcriptional regulators, such as non-coding RNAs, and in particular miRNAs is not known. Here we show using ex vivo experiments that indeed a number of miRNAs are differentially regulated in surgically removed human CB slices when acute hypoxic conditions were applied.