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Prolyl Hydroxylase Substrate Adenylosuccinate Lyase Is An Oncogenic Driver In Triple Negative Breast Cancer

ABSTRACT: Protein hydroxylation extensively regulates cellular signaling by affecting protein stability, activity, and interactome, therefore contributing to the pathogenesis of various diseases including cancers. However, because of the transient nature of the hydroxylase-substrate interaction, identifying new prolyl hydroxylation substrates remains a daunting challenge. Here, by developing a novel enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify Adenylosuccinate lyase (ADSL) as a bona fide EglN2 prolyl hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is significantly higher in TNBC than other breast cancer subtypes or normal breast tissues. Functionally, ADSL knockout greatly impairs TNBC 2-D and 3-D cell proliferation and invasiveness in vitro, as well as TNBC tumorigenesis and lung colonization in xenograft models. Mechanistically, an integrated transcriptomics and metabolomics analysis revealed that ADSL promotes the activation of the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL hydroxylation on proline 24. Specifically, hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating the oncogene cMYC protein level and its target gene expression. Our findings identify the critical role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE136414 | GEO | 2019/10/09

REPOSITORIES: GEO

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Prolyl Hydroxylase Substrate Adenylosuccinate Lyase Is An 2 Oncogenic Driver In Triple Negative Breast Cancer

Project description:Protein hydroxylation extensively regulates cellular signaling by affecting protein stability, activity, and interactome, therefore contributing to the pathogenesis of various diseases including cancers. However, because of the transient nature of the hydroxylase-substrate interaction, identifying new prolyl hydroxylation substrates remains a daunting challenge. Here, by developing a novel enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify Adenylosuccinate lyase (ADSL) as a bona fide EglN2 prolyl hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is significantly higher in TNBC than other breast cancer subtypes or normal breast tissues. Functionally, ADSL knockout greatly impairs TNBC 2-D and 3-D cell proliferation and invasiveness in vitro, as well as TNBC tumorigenesis and lung colonization in xenograft models. Mechanistically, an integrated transcriptomics and metabolomics analysis revealed that ADSL promotes the activation of the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL hydroxylation on proline 24. Specifically, hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating the oncogene cMYC protein level and its target gene expression. Our findings identify the critical role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.

2019-11-20 | PXD015790 | Pride

Prolyl Hydroxylase Substrate Adenylosuccinate Lyase Is An Oncogenic Driver In Triple Negative Breast Cancer

Project description:Protein hydroxylation extensively regulates cellular signaling by affecting protein stability, protein-protein interaction and protein activity, and its dysregulation contributes to the pathogenesis of various diseases including cancers. However, because of the transient nature of the enzyme-substrate interaction, identifying new prolyl hydroxylation substrates remains a daunting challenge. Here, by developing a novel substrate-trapping strategy combining tumor hypoxia and hydroxylase pharmacological inhibition with TAP-TAG purification followed by mass spectrometry, we identify ADSL as a bona fide EglN2 prolyl hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is significantly higher in TNBC than in the other breast cancer subtypes and normal breast tissues. Functionally, ADSL knock out greatly impairs TNBC 2-D and 3-D cell proliferation and invasiveness in vitro, as well as TNBC tumorigenesis and metastasis in xenograft models. Mechanistically, the integrated transcriptome and metabolome analysis reveals that ADSL promotes the activation of the oncogene cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL hydroxylation. Specifically, ADSL, by affecting adenosine levels, controls the expression of the long non-coding RNA MIR22HG, which negatively regulates the oncogene cMYC protein level and, thus, cMYC target gene expression. Our findings identify ADSL and ADSL hydroxylation as potential therapeutic targets in TNBC.

2020-10-06 | PXD015773 | Pride

Prolyl Hydroxylase Substrate Adenylosuccinate Lyase Is An Oncogenic Driver In Triple Negative Breast Cancer

2020-10-02 | MSV000086231 | MassIVE

Histone H3 proline 16 hydroxylation regulates mammalian gene expression [RNA-Seq]

Project description:Histone posttranslational modifications (PTMs) are important for regulating various DNA-templated processes. Emerging evidence suggests a critical involvement of the previously less-explored histone PTMs in gene activity regulation. Here, we report the existence of a new histone PTM in the mammalian cells, hydroxylation of H3 proline 16 (H3P16-OH) catalyzed by EglN2, a proline hydroxylase. We show that EglN2-mediated H3P16-OH enhances direct binding of Lysine-Specific Demethylase 5A (KDM5A) with its substrate, H3 lysine 4 trimethylation (H3K4me3), resulting in enhanced chromatin recruitment of KDM5A and decrease of H3K4me3 at target genes. Genome-wide mapping by CUT&RUN in multiple mammalian cell models reveals a functional connection between EglN2, H3P16-OH, KDM5A and H3K4me3. Integrated analysis with RNA-Seq also identifies distinct subsets of genes that are regulated through H3P16-OH in different cell lines. This study therefore demonstrates a new player of the “histone code” by revealing a role of H3P16-OH in regulating gene expression in mammalian cells.

2022-08-02 | GSE179112 | GEO

Histone H3 proline 16 hydroxylation regulates mammalian gene expression [CUT&RUN]

2022-08-02 | GSE179108 | GEO

Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response.

Project description:The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating inflammatory responses and cellular metabolism. Both neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration leading to amyotrophic lateral sclerosis (ALS) and correlate with disease progression. Therefore, the aim of this study was to explore the role of EGLN2 in ALS. Using a genetic and an oligonucleotide-based approach, we showed that downregulation of EGLN2 protects motor neurons and mitigates the ALS-like phenotypes in a mouse and a zebrafish model of ALS. Single-nuclei RNA sequencing of murine spinal cord revealed that loss of EGLN2 induced an astrocyte-specific downregulation of pro-inflammatory interferon-stimulated genes. In addition, we found that genetic deletion of EGLN2 restored the disturbed interferon response in iPSC-derived astrocytes from an ALS patient, confirming the novel link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a potential novel ALS therapeutic target normalizing the astrocytic interferon-dependent inflammatory axis in vivo as well as in patient-derived cells.

2024-09-05 | GSE260913 | GEO

Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response

2024-09-09 | GSE219201 | GEO

Lack of activity of recombinant HIF prolyl hydroxylases (PHDs) on reported non-HIF substrates

Project description:Hypoxia Inducible Factor (HIF) prolyl hydroxylase domain (PHD) enzymes catalyse the posttranslational hydroxylation of conserved prolyl residues in the alpha-subunit of the HIF transcription factor. These modifications, which promote the degradation of HIF-alpha subunits by the pVHL E3 ligase complex and impart oxygen-dependent regulation of the HIF transcriptional response, have been extensively characterised at the molecular, cellular and organismal level. Since the discovery of the PHDs, a range of less well-characterised non-HIF substrates have been reported with the potential to confer oxygen-sensitivity to a diverse range of cellular processes. We sought to systematically compare all of the reported non-HIF substrates for their ability to support PHD-catalysed hydroxylation. We performed a comprehensive series of in vitro hydroxylation assays reacting synthetic peptides and full-length protein substrates generated by in vitro transcription and translation with purified recombinant enzyme preparations. Prolyl hydroxylation was assayed directly by mass spectrometry and radiochemical assay for hydroxyproline. Both methods enabled quantitative appraisal of enzyme-catalysed hydroxylation, with liquid chromatography mass spectrometry methods employing NMR-quantified peptide standards to calibrate retention time signatures and determine ionisation efficiencies for each target peptide. Using these approaches we assayed hydroxylation on 23 different proteins. Surprisingly, we did not detect measurable hydroxylation on any of the reported non-HIF substrates using either method. In contrast, control assays with HIF1-alpha substrate supported high stoichiometry (typically >90%) hydroxylation. Our findings suggest that PHD substrates are more restricted than has been reported.

2019-08-30 | PXD013112 | Pride

Proline hydroxylation of collagens in prolyl 4-hydroxylase mutant mice

Project description:Collagen from the skin of wild type and prolyl 4-hydroxylase mutant mice was extracted and proline hydroxylation of the collagen-derived peptides were analyzed by LC-MS/MS.

2018-04-10 | PXD008802 | Pride

Chromophobe and Oncocytoma Renal Cell Carcinomas: gene expression and SNP analysis

Project description:Chromosomal abnormalities, such as structural and numerical abnormalities, are a common occurrence in cancer. The close association of homologous chromosomes during interphase, a phenomenon termed somatic chromosome pairing, has been observed in cancerous cells, but the functional consequences of somatic pairing have not been established. Gene expression profiling studies revealed that somatic pairing of chromosome 19 is a recurrent chromosomal abnormality in renal oncocytoma, a neoplasia of the adult kidney. Somatic pairing was associated with significant disruption of gene expression within the paired regions and resulted in the deregulation of the prolyl-hydroxylase EGLN2, a key protein that regulates the oxygen-dependent degradation of hypoxia-inducible factor (HIF). Overexpression of EGLN2 in renal oncocytoma increased ubiquitin-mediated destruction of HIF and concomitantly suppressed the expression of several HIF-target genes, including the pro-death BNIP3L gene. The transcriptional changes that are associated with somatic pairing of chromosome 19 mimic the transcriptional changes that occur following DNA amplification. Therefore, in addition to numerical and structural chromosomal abnormalities, alterations in chromosomal spatial dynamics should be considered as genomic events that are associated with tumorigenesis. The identification of EGLN2 as a significantly deregulated gene that maps within the paired chromosome region directly implicates defects in the oxygen-sensing network to the biology of renal oncocytoma. Keywords: Gene expression profiling, SNP analysis, renal, tumor Oncocytoma and Chromophobe RCC samples - expression profiling and SNP chip analysis

2010-05-25 | E-GEOD-8271 | biostudies-arrayexpress

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