Oxygen concentration in prostate cancer tissue is significantly low, i.e. ~0.3% O2. This study showed that pathological hypoxia (<0.5% O2) increased the expression of androgen receptor (AR) target genes such as prostate-specific antigen (PSA) and kallikrein-related peptidase 2 in LNCaP human prostate cancer cells by modifying the quantity and activity of related Jumonji C domain-containing histone demethylases (JMJDs). Under pathological hypoxia, the catalytic activities of JMJD2A, JMJD2C and Jumonji/ARID domain-containing protein 1B (JARID1B) were blocked due to the lack of their substrate, i.e. oxygen. Chromatin immunoprecipitation analyses showed that hypoxia increased the appearance of H3K9me3 and H3K4me3, substrates of JMJD2s and JARID1B, respectively, in the PSA enhancer. In contrast, JMJD1A, which demethylates both H3K9me2 and H3K9me1, maintained its catalytic activity even under severe hypoxia. Furthermore, hypoxia increased the expression of JMJD1A. Hypoxia and androgen additively increased the recruitment of JMJD1A and p300 on the enhancer region of PSA through interaction with the hypoxia-inducible factor-1α and AR, both of which bind the PSA enhancer. Thus, hypoxia enhanced the demethylation of H3K9me2 and H3K9me1, leading to provide unmethylated H3K9 residues that are substrates for histone acetyltransferase, p300. Consequently, hypoxia increased the acetylation of histones of the PSA enhancer, which facilitates its transcription.
Hypoxia-Inducible Factor (HIF)-1α/β heterodimer is a master transcription factor for several genes involved in angiogenesis, glycolysis, pH balance and metastasis. These HIF-1 target genes help tumors to overcome forthcoming metabolic obstacles as they grow. Under normoxic condition, the HIF-1α subunit is hydroxylated by its specific prolyl-4 hydroxylase 2, given the acronym PHD2. Hydroxylated HIF-1α becomes a target for von Hippel-Lindau (VHL), which functions as an E3 ubiquitin ligase. Src prevents hydroxylation-dependent ubiquitinylation of HIF-1α, thus stabilizing it under normoxic conditions. We found that active Src does not directly phosphorylate any tyrosine residue of PHD2. In vitro hydroxylation reaction showed that the presence of the purified active Src protein does not inhibit the hydroxylation activity of the purified PHD2 enzymes. Instead of directly inhibiting PHD2, Src recruits several downstream-signaling pathways to intercept hydroxylation-dependent ubiquitinylation of HIF-1α. Using biochemical and genetic inhibition, we demonstrated that Src requires reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/Rac complex for stabilization of HIF-1α. We found that excess vitamin C treatment attenuates Src-induced HIF-1α activation. HIF-1α-hydroxylation-dependent VHL pull-down assay showed that Src inhibits cellular PHD2 activity by inducing ROS production in a mechanism involving Rac1-dependent NADPH oxidase. Src-induced ROS reduces cellular vitamin C, which is required for the activity of PHD2, thus Src can block VHL recruitment of HIF-1α, leading to stabilization of HIF-1α.
Hypoxia increases both active and repressive histone methylation levels via decreased activity of histone demethylases. However, how such increases coordinately regulate induction or repression of hypoxia-responsive genes is largely unknown. Here, we profiled active and repressive histone tri-methylations (H3K4me3, H3K9me3, and H3K27me3) and analyzed gene expression profiles in human adipocyte-derived stem cells under hypoxia. We identified differentially expressed genes (DEGs) and differentially methylated genes (DMGs) by hypoxia and clustered the DEGs and DMGs into four major groups. We found that each group of DEGs was predominantly associated with alterations in only one type among the three histone tri-methylations. Moreover, the four groups of DEGs were associated with different TFs and localization patterns of their predominant types of H3K4me3, H3K9me3 and H3K27me3. Our results suggest that the association of altered gene expression with prominent single-type histone tri-methylations characterized by different localization patterns and with different sets of TFs contributes to regulation of particular sets of genes, which can serve as a model for coordinated epigenetic regulation of gene expression under hypoxia.
Activation of Raf reduces the repressive histone mark H3K27me3 at the INK4a locus by inducing the H3K27me3 demethylase JMJD3. During hypoxia, the catalyitc activity of JMJD3 is reduced due to the limited availability of O 2 as a substrate. In our study, we found that hypoxia prevented Raf-induced JMJD3 from demethylating H3K27me3 at the INK4a locus. Nonetheless, hypoxia did not prevent Raf signaling from inducing INK4a mRNA. Interestingly, we found that hypoxia strongly enhanced the active histone mark H3K4me3 at the INK4a locus by inhibiting the H3K4me3 demethylases JARID1A and JARID1B. Therefore, this study demonstrates that the O 2 concentration in the microenvironment differentially affects the repressive methylation on K27 and the activating methylation on K4 at the INK4a locus by inhibiting the H3K27me3 and H3K4me3 demethylases.
We previously found that clioquinol (CQ) increases functional hypoxia-inducible factor-1α (HIF-1α) with enhanced transcription of its target genes. Here we report that compounds derived from 8-hydroxyquinoline including CQ, broxyquinoline (BQ), iodoquinol (IQ) and chloroacetoxyquinoline (CAQ) promote neovascularization effectively based on chick chorioallantoic membrane assays. The CQ analogues induce stabilization of HIF-1α as well as enhance HIF-1-mediated vascular endothelial growth factor transcription. These analogues also exert inhibitory effects on the activity of prolyl and asparaginyl hydroxylations of HIF-1α in vitro. Despite metal ion-dependent restoration of the inhibited HIF-1α hydroxylase activity, the cellular HIF-1α-inducing effects of the CQ analogues are reversed to varying degrees by Key words 8-hydroxyquinoline derivative; hypoxia-inducible factor-1α; zinc ion; prolyl hydroxylase domain 2; factor-inhibiting hypoxia-inducible factor-1; angiogenesis Hypoxia-inducible factor-1 (HIF-1) mediates a ubiquitous pathway by which mammalian cells sense and respond to hypoxia.1,2) As a complex of α and β subunits, it triggers transcriptional activation of oxygen-regulated genes implicated in embryonic development, angiogenesis, erythropoiesis, and glycolysis. [3][4][5][6][7][8] A number of studies reveal that HIF is also involved in the pathophysiology of many disease states including cerebral and pulmonary ischemia, cancer tumorigenesis, and metastasis.9-12) Accordingly, the activation of HIF-1 dependent responses and the subsequent transcription of its target genes have been predicted to help patients with systemic or local tissue hypoxia. 13)The HIF signaling pathway is a multi-step process initiated at the level of HIF-1 stability. HIF-1α is rapidly degraded under normoxic conditions. 14,15) The von Hippel-Lindau tumor suppressor protein (VHL) binds directly to HIF-1α for ubiquitination followed by proteasomal degradation. [16][17][18] Because the interaction between VHL and HIF-1α is strictly dependent on the hydroxylation of proline residues of HIF-1α, oxygen deprivation under hypoxia reduces HIF-1α turnover by decreasing proline hydroxylation, leading to accumulation of unmodified 20) Stabilized HIF-1α then translocates into the nucleus and recruits coactivators CBP/p300 as a heterodimer with the β subunit, which specifically recognizes the hypoxiaresponsive element (HRE) to activate target gene transcription. The transcriptional activity of HIF is modulated under normoxia separately by asparaginyl hydroxylation of HIF-1α that blocks its interaction with CBP/p300. 6,21) Both prolyl (prolyl hydroxylase domain; PHD) and asparaginyl hydroxylases (factor-inhibiting hypoxia-inducible factor-1; FIH-1) belong to the superfamily of 2-oxoglutarate (2-OG)-dependent non-heme iron dioxygenases, which require oxygen as a co-substrate, providing the molecular basis for their oxygen-sensing function. [22][23][24] 8-Hydroxyquinoline (8-HQ) is a lipophilic agent that forms a stable five-membered chelate ring with ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.