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SEVERE CONSEQUENCES OF A HIGH-LIPID DIET INCLUDE HYDROGEN SULFIDE DYSFUNCTION AND DISEASE AGGRESSION IN GLIOBLASTOMA

ABSTRACT: Glioblastoma (GBM) remains among the deadliest of human malignancies, and the emergence of the cancer stem cell (CSC) phenotype represents a major challenge to durable treatment response. Because the environmental and lifestyle factors that impact CSC populations are not clear, we sought to understand the consequences of diet on CSC enrichment. We evaluated disease progression in mice fed an obesity-inducing high-fat diet (HFD) versus a low-fat, control diet. HFD resulted in hyper-aggressive disease accompanied by CSC enrichment and shortened survival. HFD drove intracerebral accumulation of saturated fats, which inhibited the production of the cysteine metabolite and gasotransmitter, hydrogen sulfide (H2S). H2S functions principally through protein S-sulfhydration and regulates multiple programs including bioenergetics and metabolism. Inhibition of H2S increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to death of cultured GBM cells and stasis of GBM tumors in vivo. GBM specimens present an overall reduction in protein S-sulfhydration, primarily associated with proteins regulating cellular metabolism. These findings provide new evidence that diet modifiable H2S signaling serves to suppress GBM by restricting metabolic fitness, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Glioblastoma

SUBMITTER: Nazmin Bithi

LAB HEAD: Christopher Hine

PROVIDER: PXD025902 | Pride | 2021-05-25

REPOSITORIES: Pride

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Dietary restriction transforms the mammalian protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

Project description:Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation on relatively few identified proteins, tissue-specific sulfhydrome profiles and their associated functions are not well characterized, specifically under conditions known to modulate H2S production. We hypothesized that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific sulfhydromes. Here, we found protein persulfidation was enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking H2S producing enzyme cystathionine γ-lyase (CGL) had overall decreased tissue protein persulfidation and failed to functionally augment sulfhydromes in response to DR. Overall, we defined tissue- and CGL-dependent sulfhydromes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.

2021-01-25 | PXD022954 | Pride

Dietary restriction transforms the mammalian protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

2021-01-25 | PXD022956 | Pride

Dietary restriction transforms the mammalian protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

2021-01-25 | PXD022888 | Pride

Peripubertal Bisphenol A Exposure Imparts Detrimental Acute and Aging-Related Changes in Body Composition, Cognition, and H2S Production and Signaling

Project description:Peripubertal endocrine disruption has immediate and lifelong consequences on health, cognition, and lifespan. Disruption comes from dietary, environmental, and pharmaceutical sources. The plasticizer Bisphenol A (BPA) is one such endocrine disrupting chemical (EDC). However, it’s unclear if peripubertal BPA exposure incites long-lasting physiological, neuro-cognitive, and/or longevity-related metabolic impairments. Catabolism of cysteine via transsulfuration enzymes produces hydrogen sulfide (H2S), a redox-modulating gasotransmitter causative to endocrine and metabolic homeostasis and improved cognitive function with age. As thyroid hormone (TH) regulates hepatic H2S production and BPA is a TH receptor antagonist, we hypothesized BPA exposure during peripubertal development impairs metabolic and neuro-cognitive/behavioral endpoints in aged mice, in part, due to altered peripheral H2S production. Results: To test this, male C57BL/6J mice at 5 weeks of age were orally exposed for 5 weeks to 250 ug BPA/kg defined as low dose group (LD BPA), or 250 mg BPA/kg defined as high dose group (HD BPA). Both LD and HD BPA exposure decreased lean mass and increased fat mass. These changes were accompanied by decreased serum total TH. Additionally, LD BPA had an anxiogenic effect while HD BPA caused cognitive deficits. Notably, HD BPA attenuated renal H2S production both acutely and during aging, which correlated with spatial memory deficits. Innovation and Conclusion: These findings provide a potential mechanism of action for the acute and long-term health impacts of BPA-induced peripubertal endocrine disruption and bolster the need for improved monitoring and limitation of adolescent BPA exposure.

2021-05-25 | PXD025746 | Pride

SEVERE CONSEQUENCES OF A HIGH-LIPID DIET INCLUDE HYDROGEN SULFIDE DYSFUNCTION AND DISEASE AGGRESSION IN GLIOBLASTOMA

Project description:Glioblastoma (GBM) remains among the deadliest of human malignancies, and the emergence of the cancer stem cell (CSC) phenotype represents a major challenge to durable treatment response. Because the environmental and lifestyle factors that impact CSC populations are not clear, we sought to understand the consequences of diet on CSC enrichment. We evaluated disease progression in mice fed an obesity-inducing high-fat diet (HFD) versus a low-fat, control diet. HFD resulted in hyper-aggressive disease accompanied by CSC enrichment and shortened survival. HFD drove intracerebral accumulation of saturated fats, which inhibited the production of the cysteine metabolite and gasotransmitter, hydrogen sulfide (H2S). H2S functions principally through protein S-sulfhydration and regulates multiple programs including bioenergetics and metabolism. Inhibition of H2S increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to death of cultured GBM cells and stasis of GBM tumors in vivo. GBM specimens present an overall reduction in protein S-sulfhydration, primarily associated with proteins regulating cellular metabolism. These findings provide new evidence that diet modifiable H2S signaling serves to suppress GBM by restricting metabolic fitness, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.

2021-05-25 | PXD023685 | Pride

Quantitative profiling of protein sulfhydrome by the BTA-TMT

Project description:The redox-based modification of cysteine residues in proteins regulates their function in many biological processes. The gas molecule H2S has been shown to sulfhydrate redox sensitive cysteine residues resulting in an H2S-modified proteome known as the sulfhydrome. Tandem Mass Tags (TMT) multiplexing strategies for large-scale proteomic analyses have become increasingly prevalent. Here we developed TMT-based proteomics approach for selectively trapping and tagging cysteine persulfides in the cellular proteomes. With this approach, we revealed the natural protein sulfhydrome of two human cell lines, and identified insulin as novel sulfhydration substrate in pancreatic beta cells. Moreover, we identified metabolic pathways selectively being targets for H2S. Using this approach, we found that the enzymes involved in cellular energy pathway are primarily subjected to a Redox Thiol Switch (RTS), which is a switch of one modification to another on the same cysteine residue. We further showed that protein S-glutathioinylation, a specific reversible thiol modification in cysteine residues under oxidative stress conditions, which can be switched to S-sulfhydration. We propose that a RTSGS from S-glutathioinylation to S-sulfhydration is a key mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.

2020-03-09 | PXD015307 | Pride

Homo sapiens

Project description:CD133+ and CD133- CSC lines in primary human GBM

| PRJNA98331 | ENA

Genome-wide Definition of the SigF Regulon in Mycobacterium tuberculosis (ChIP-chip)

Project description:The genome wide ChIP-on-chip analysis to identify the DNA binding sites for the M.tuberculosis sigma factor Rv3286c (SigF) SigF binding sites were determined by microarray analysis of anti-sigF immunoprecipitated DNA from H37Rv(ΔrsbW/sigF)::pmySigF compared to H37Rv(ΔrsbW/sigF)::pMY769 (both cultured with pristinamycin for 3 days). 4 biological replicates were performed.

2012-01-20 | E-GEOD-34919 | biostudies-arrayexpress

ChIP-seq of E. coli to identify H-NS and Fis binding at multiple time-points during growth in rich medium

Project description:Among the most important regulators of gene expression in bacteria are 'nucleoid-associated proteins'. These proteins alter the topology of the bound DNA by bending, wrapping or bridging it, thus having multiple effects, including transcriptional regulation, on the bacterial cell. Among the best-studied nucleoid proteins are H-NS and Fis, which bind to specific sequences on the DNA. H-NS is a global repressor of gene expression. Fis alters the global conformation of the DNA by introducing branched structures in it; but its effect on gene expression on a genomic scale remains largely unclear.<br><br>Several bacterial transcriptional regulators including H-NS and Fis have been studied using ChIP-chip. However, the higher resolution and dynamic range offered by ChIP-Seq have not been exploited for any bacterial species. By performing ChIP-Seq of these two proteins, we present the first such study in a bacterium. In addition to providing a proof-of-principle for the use of this technology for bacteria, we perform our study at multiple time-points during growth in rich medium, thus generating new insights into how these proteins function under different cellular conditions. Further, by analysing our data in conjunction with newly-generated gene expression and RNA polymerase-chromosome interaction data we provide new interpretation of the genome-scale patterns of the interactions of these proteins to the DNA.

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Chromatin immunoprecipitation of yeast to identify genomic binding locations of yeast transcription machinary factors Reb1, Rpb3, Rpo21, Rsc9, Sua7 and Swr1

Project description:High-resolution genome-wide mapping of the yeast transcription machinery. ChIP-chip was performed to identify the genomic binding locations for each factor. <br><br>Processed data files are also available on the FTP server for this experiment.

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