Nitric oxide regulates gene expression in cancers by controlling histone posttranslational modifications
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ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE66324 | GEO | 2015/11/05
SECONDARY ACCESSION(S): PRJNA276553
REPOSITORIES: GEO
Similar Datasets
Project description:Altered nitric oxide (•NO) metabolism underlies cancer pathology, but mechanisms explaining many •NO-associated phenotypes remain unclear. We have found that cellular exposure to •NO changes histone posttranslational modifications (PTM) by directly inhibiting the catalytic activity of JmjC-domain containing histone demethylases. Herein, we describe how •NO exposure links modulation of histone PTMs to gene expression changes that promote oncogenesis. Through high-resolution mass spectrometry, we generated an extensive map of •NO-mediated histone PTM changes at 15 critical lysine residues on the core histones H3 and H4. Concomitant microarray analysis demonstrated that exposure to physiologic •NO resulted in the differential expression of over 6,500 genes in breast cancer cells. Measurements of the association of H3K9me2 and H3K9ac across genomic loci revealed that differential distribution of these particular PTMs correlated with changes in the level of expression of numerous oncogenes, consistent with epigenetic code. Our results establish that •NO functions as an epigenetic regulator of gene expression mediated by changes in histone PTMs.
| S-EPMC4681644 | biostudies-literature
Project description:Dynamic changes in histone posttranslational modifications (PTMs) are important regulators of chromatin structure and gene transcription in both normal and disease settings. Herein, we describe a novel signaling mechanism of nitric oxide (â?¢NO) by demonstrating its ability to modulate gene expression via alteration of histone PTMs. Having established that â?¢NO exposure induced differential expression of approximately 6500 genes, we set out to determine if there was an epigenetic component to their regulation. â?¢NO exposure led to alterations in the global levels of acetyl and methyl modifications at numerous lysine residues on core histones H3 and H4. Residues H3K9me2/ac were examined further and determined to have differential distribution at various loci throughout the genome in response to â?¢NO. Changes in the enrichment levels of H3K9me2/ac at specific genes correlated with changes in the expression levels of their transcripts. Molecular mechanisms contributing to phenotypic outcomes in â?¢NO-associated cancers remain to be well understood since traditional modes of â?¢NO-signaling do not explain a large proportion of its impact on tumor cell behavior. Our results reveal that â?¢NO drives a significant amount of gene expression changes epigenetically by changing the distribution of numerous histone marks. Cultured cells were treated with 500uM DETA/NO to examine the effects of a physiologically relevant â?¢NO concentration on gene expression. A total of two untreated biological replicates and two â?¢NO-treated biological replicates were harvested. The untreated samples served as control against which comparisons were made to elucidate â?¢NO-mediated changes in the gene expression.
2015-11-05 | E-GEOD-66322 | biostudies-arrayexpress
Project description:Dynamic changes in histone posttranslational modifications (PTMs) are important regulators of chromatin structure and gene transcription in both normal and disease settings. Herein, we describe a novel signaling mechanism of nitric oxide (•NO) by demonstrating its ability to modulate gene expression via alteration of histone PTMs. Having established that •NO exposure induced differential expression of approximately 6500 genes, we set out to determine if there was an epigenetic component to their regulation. •NO exposure led to alterations in the global levels of acetyl and methyl modifications at numerous lysine residues on core histones H3 and H4. Residues H3K9me2/ac were examined further and determined to have differential distribution at various loci throughout the genome in response to •NO. Changes in the enrichment levels of H3K9me2/ac at specific genes correlated with changes in the expression levels of their transcripts. Molecular mechanisms contributing to phenotypic outcomes in •NO-associated cancers remain to be well understood since traditional modes of •NO-signaling do not explain a large proportion of its impact on tumor cell behavior. Our results reveal that •NO drives a significant amount of gene expression changes epigenetically by changing the distribution of numerous histone marks.
2015-11-05 | GSE66322 | GEO
Project description:Dynamic changes in histone posttranslational modifications (PTMs) are important regulators of chromatin structure and gene transcription in both normal and disease settings. Herein, we describe a novel signaling mechanism of nitric oxide (â¢NO) by demonstrating its ability to modulate gene expression via alteration of histone PTMs. Having established that â¢NO exposure induced differential expression of approximately 6500 genes, we set out to determine if there was an epigenetic component to their regulation. â¢NO exposure led to alterations in the global levels of acetyl and methyl modifications at numerous lysine residues on core histones H3 and H4. Residues H3K9me2/ac were examined further and determined to have differential distribution at various loci throughout the genome in response to â¢NO. Changes in the enrichment levels of H3K9me2/ac at specific genes correlated with changes in the expression levels of their transcripts. Molecular mechanisms contributing to phenotypic outcomes in â¢NO-associated cancers remain to be well understood since traditional modes of â¢NO-signaling do not explain a large proportion of its impact on tumor cell behavior. Our results reveal that â¢NO drives a significant amount of gene expression changes epigenetically by changing the distribution of numerous histone marks. Cultured cells were treated with 500uM DETA/NO to examine the effects of a physiologically relevant â¢NO concentration on differential distribution of H3K9ac/H3K9me2. A total of two untreated biological replicates and two â¢NO-treated biological replicates were harvested. The untreated samples served as control against which comparisons were made to elucidate â¢NO-mediated changes in the histone landscape.
2015-11-05 | E-GEOD-66318 | biostudies-arrayexpress
Project description:Dynamic changes in histone posttranslational modifications (PTMs) are important regulators of chromatin structure and gene transcription in both normal and disease settings. Herein, we describe a novel signaling mechanism of nitric oxide (•NO) by demonstrating its ability to modulate gene expression via alteration of histone PTMs. Having established that •NO exposure induced differential expression of approximately 6500 genes, we set out to determine if there was an epigenetic component to their regulation. •NO exposure led to alterations in the global levels of acetyl and methyl modifications at numerous lysine residues on core histones H3 and H4. Residues H3K9me2/ac were examined further and determined to have differential distribution at various loci throughout the genome in response to •NO. Changes in the enrichment levels of H3K9me2/ac at specific genes correlated with changes in the expression levels of their transcripts. Molecular mechanisms contributing to phenotypic outcomes in •NO-associated cancers remain to be well understood since traditional modes of •NO-signaling do not explain a large proportion of its impact on tumor cell behavior. Our results reveal that •NO drives a significant amount of gene expression changes epigenetically by changing the distribution of numerous histone marks.
2015-11-05 | GSE66318 | GEO
Project description:Dynamic changes in histone posttranslational modifications (PTMs) are important regulators of chromatin structure and gene transcription in both normal and disease settings. Herein, we describe a novel signaling mechanism of nitric oxide (•NO) by demonstrating its ability to modulate gene expression via alteration of histone PTMs. Having established that •NO exposure induced differential expression of approximately 6500 genes, we set out to determine if there was an epigenetic component to their regulation. •NO exposure led to alterations in the global levels of acetyl and methyl modifications at numerous lysine residues on core histones H3 and H4. Residues H3K9me2/ac were examined further and determined to have differential distribution at various loci throughout the genome in response to •NO. Changes in the enrichment levels of H3K9me2/ac at specific genes correlated with changes in the expression levels of their transcripts. Molecular mechanisms contributing to phenotypic outcomes in •NO-associated cancers remain to be well understood since traditional modes of •NO-signaling do not explain a large proportion of its impact on tumor cell behavior. Our results reveal that •NO drives a significant amount of gene expression changes epigenetically by changing the distribution of numerous histone marks.
2015-11-05 | GSE66323 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-12-01 | GSE216952 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-09-23 | E-GEOD-49219 | biostudies-arrayexpress
Project description:Nitric oxide (NO) is an essential signaling molecule in the body, regulating numerous biological processes. Beside its physiological roles, NO affects drug metabolism by modulating the activity and/or expression of cytochrome P450 enzymes. Previously, our lab showed that NO generation caused by inflammatory stimuli results in CYP2B6 degradation via the ubiquitin-proteasome pathway. In the current study, we tested the NO-mediated regulation of CYP2J2 that metabolizes arachidonic acids to bioactive epoxyeicosatrienoic acids, as well as therapeutic drugs such as astemizole and ebastine. To investigate the effects of NO on CYP2J2 expression and activity, Huh7 cells stably transduced with CYP2J2 with a C-terminal V5 tag were treated with dipropylenetriamine-NONOate (DPTA), a NO donor. The level of CYP2J2 proteins were decreased in a time- and concentration-dependent manner, and the activity was also rapidly inhibited. However, mRNA expression was not altered and the protein synthesis inhibitor cycloheximide did not attenuate DPTA-mediated downregulation of CYP2J2. Removal of DPTA from the culture media quickly restored the activity of remaining CYP2J2, and no further CYP2J2 degradation occurred. To determine the mechanism of CYP2J2 down-regulation by NO, cells were treated with DPTA in the presence or absence of protease inhibitors including proteasomal, lysosomal and calpain inhibitors. Remarkably, the down-regulation of CYP2J2 by NO was attenuated by calpeptin, a calpain inhibitor. However, other calpain inhibitors or calcium chelator show no inhibitory effects on the degradation. The proteasome inhibitor bortezomib showed small but significant restoration of CYP2J2 levels although stimulated ubiquitination of CYP2J2 was not detected. In conclusion, these data suggest that NO regulates CYP2J2 posttranslationally and NO-evoked CYP2J2 degradation undergoes ubiquitin-independent proteasomal degradation pathway unlike CYP2B6.
| S-EPMC5978777 | biostudies-literature
Project description:Nitric oxide (NO) regulates neuronal function and thus is critical for tuning neuronal communication. Mechanisms by which NO modulates protein function and interaction include posttranslational modifications (PTMs) such as S-nitrosylation. Importantly, cross signaling between S-nitrosylation and prenylation can have major regulatory potential. However, the exact protein targets and resulting changes in function remain elusive. Here, we interrogated the role of NO-dependent PTMs and farnesylation in synaptic transmission. We found that NO compromises synaptic function at the Drosophila neuromuscular junction (NMJ) in a cGMP-independent manner. NO suppressed release and reduced the size of available vesicle pools, which was reversed by glutathione (GSH) and occluded by genetic up-regulation of GSH-generating and de-nitrosylating glutamate-cysteine-ligase and S-nitroso-glutathione reductase activities. Enhanced nitrergic activity led to S-nitrosylation of the fusion-clamp protein complexin (cpx) and altered its membrane association and interactions with active zone (AZ) and soluble N-ethyl-maleimide-sensitive fusion protein Attachment Protein Receptor (SNARE) proteins. Furthermore, genetic and pharmacological suppression of farnesylation and a nitrosylation mimetic mutant of cpx induced identical physiological and localization phenotypes as caused by NO. Together, our data provide evidence for a novel physiological nitrergic molecular switch involving S-nitrosylation, which reversibly suppresses farnesylation and thereby enhances the net-clamping function of cpx. These data illustrate a new mechanistic signaling pathway by which regulation of farnesylation can fine-tune synaptic release.
| S-EPMC5890968 | biostudies-literature