Changes in Histone H3 acetylation in panobinostat-treated IDH-wildtype and IDH-mutant glioma cultures
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE308631 | GEO | 2025/09/19
REPOSITORIES: GEO
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Project description:IDH1/2 mutations (IDHmut) increase methylation of DNA and histones in gliomas. IDHmut inhibitors are effective against low-grade IDHmut gliomas, but new strategies against high grade IDHmut gliomas are needed. Although histone deacetylase inhibitors (HDACi) are ineffective against IDHwt glioblastoma (GBM), their potential in IDHmut gliomas has not been extensively studied. We previously established that IDHmut gliomas are more sensitive to HDACi than IDHwt GBM. Here, we show that IDHmut is associated with unique transcriptional changes mediated by the HDACi panobinostat in glioma, providing insight into the mecahnism of increased HDACi sensitivithy..
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Project description:IDH1/2 mutations (IDHmut) increase methylation of DNA and histones in gliomas. IDHmut inhibitors are effective against low-grade IDHmut gliomas, but new strategies against high grade IDHmut gliomas are needed. Although histone deacetylase inhibitors (HDACi) are ineffective against IDHwt glioblastoma (GBM), their potential in IDHmut gliomas has not been extensively studied. We previously established that IDHmut gliomas are more sensitive to HDACi than IDHwt GBM. Here we show that IDHmut is associated with greater sensitivity to HDACi only in glioma, not in IDHmut chondrosarcoma or cholangiocarcinoma. Two mediators of HDACi resistance, YAP and TAZ, were methylated and suppressed in IDHmut gliomas, but not in other IDHmut cancers. Inducing YAP or TAZ expression in IDHmut gliomas conferred resistance to HDACi. Here, we report the transcriptional changes mediated by the HDACi belinostat in IDHmut glioma with and without YAP or TAZ expression.
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Project description:Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histological progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution towards an IDHwt-like phenotype.
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Project description:Gliomas are an incurable malignancy of the central nervous system. Patients that present with this disease have poor prognosis, necessitating the development of new therapeutic approaches. Glioblastoma is the most aggressive form of the disease and although lower grade gliomas have an intially better prognosis, they often progress to high grade glioma. Immunotherapy has been successful in other solid malignancies, but has not demonstrated efficacy in gliomas. Isocitrate dehydrogenase (IDH) is mutated in the majority of lower grade gliomas, and differences in the microenvironment between IDHmut and IDHwt disease contribute to differences in antitumor immunity. However, it remains unknown whether there are similiarites or differences between the immune landscape of IDHmut versus IDHwt gliomas. To address this question, we generated single-cell RNAseq data from 19 patients with grade II-IV glioma, of which 13 were IDHwt and 6 were IDHmut.
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Project description:High-grade gliomas are malignant neuroepithelial tumors. The current WHO classification for adult-type diffuse gliomas is based on IDH1/2 mutational and 1p/19q-codeletion status, which can be refined by emerging genomics, transcriptomics, and methylomics approaches. Nevertheless, therapy has been dominated by radiochemotherapy for about 15 years and progressed little in efficacy or precision through advanced molecular patient stratification. Glioma proteome alterations remain undercharacterized despite their promise for a better stratification and, in particular, the identification of therapeutic targets. Here, we used mass spectrometry (MS) to characterize 42 formalin-fixed, paraffin-embedded (FFPE) samples from IDH-wildtype (IDHwt), IDH-mutant (IDHmut) gliomas with and without 1p/19q-codeletion, and non-neoplastic brain tissue controls. Based on more than 5500 quantified proteins and 5000 phospho-sites, gliomas separated according to IDH1/2 mutational status and reflected loss of proteins encoded on 1p/19q in IDHmut, gains on chromosome 7 and losses on chromosome 10 in IDHwt. Unexpectedly, the 1p/19q-codeletion resulted in minor proteome changes. Instead, two proteomic subtypes of IDHmut gliomas showed major perturbations of mitochondrial DNA-encoded proteins, aerobic/anaerobic energy metabolism, RNA metabolism, chromatin dynamics, the extracellular matrix as well as tumor suppressor and oncoproteins. Reanalysis of three glioma proteomics studies independently validate the observed hallmarks and associate these proteomic subtypes with the well-established proneural and classic/mesenchymal IDHwt glioma subtypes. These results suggest an alternative stratification of IDHmut gliomas as part of common phenotypic subtypes independent of the IDH status, with broad therapeutic implications for patients with IDHmut gliomas in the future. Altogether, our study provides a rich protein and phospho-site resource restratifying glioma subtypes and supporting future mechanism of action and target discovery investigations.
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Project description:Glial cell-derived brain tumors (gliomas) are devastating diseases without effective curative therapies. Gliomas are classified according to various schemes including the cancer-initiating cell type, World Health Organization tumor grades, and genetic markers such as Isocitrate dehydrogenase (IDH) mutations and chromosomal 1p/19q codeletion status. Genomics, transcriptomics and methylomics approaches are emerging as powerful means to refine classification. However, various aspects of cancer biology are solely reflected on the proteomelevel. Here, we employ mass spectrometry (MS) to characterize the proteomes and phospho-proteomes of IDHmut glioma entities with and without 1p/19q codeletion, IDHwt gliomas and control tissue from a total of 42 patients. Our data-dependent acquisition MS workflow on average quantifies more than 5000 proteins and 3000 phospho-sites per sample of formalin-fixed paraffin-embedded (FFPE) brain sections. The tumor proteomes reflected genetic alterations such as the loss of chromosome 1p/19q proteins, the loss of ATRX in non-codeletion IDHmut glioma, and the frequent loss and amplification of chromosomes 10 and 7, respectively,in IDH-wild type glioma. Nevertheless, 1p/19q codeletion status was not the major determinant of IDHmut glioma proteomes. Instead, the proteome profiles suggest an alternative classification of IDHmut gliomas that correlates with the loss of mitochondrial DNA-encoded proteins, the abundance of respiratory chain proteins, a distinct tumor suppressor and oncoprotein profile, an extracellular matrix signature, and alterations in the phospho-proteome. Moreover, the glioma association of numerous proteins implicated in other cancers by this dataset provides a resource for further mechanistic investigation of glioma genesis and progression.
2022-11-09 | PXD024427 | Pride
Project description:<p>Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring an isocitrate dehydrogenase 1 mutation (IDHmut), acquire a different tumor biology and clinical manifestation than those that are IDHWT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we discovered monounsaturated (MUFA) to polyunsaturated (PUFA) lipid imbalances in organelles, generated by IDH mutation in cells and patient tissue, that were responsible for Golgi and ER dilation. We demonstrated a direct link between the IDH mutation and these organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate limiting enzyme in MUFA biosynthesis. Inhibition of IDH mutation or SCD silencing restored ER and Golgi morphology, while D-2HG and oleic acid induced morphological defects in these organelles. Moreover, addition of oleic acid, which tilted the balance towards elevated levels of MUFA, produced IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the biodistribution of lipids in the organelles of glioma, providing a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.</p><p><br></p><p>Linked studies;</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1973/' rel='noopener noreferrer' target='_blank'>MTBLS1973</a> LCMS(CSHNeg)</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1974' rel='noopener noreferrer' target='_blank'>MTBLS1974</a> LCMS(CSHPos)</p>
2020-11-24 | MTBLS1967 | MetaboLights
Project description:<p>Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring an isocitrate dehydrogenase 1 mutation (IDHmut), acquire a different tumor biology and clinical manifestation than those that are IDHWT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we discovered monounsaturated (MUFA) to polyunsaturated (PUFA) lipid imbalances in organelles, generated by IDH mutation in cells and patient tissue, that were responsible for Golgi and ER dilation. We demonstrated a direct link between the IDH mutation and these organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate limiting enzyme in MUFA biosynthesis. Inhibition of IDH mutation or SCD silencing restored ER and Golgi morphology, while D-2HG and oleic acid induced morphological defects in these organelles. Moreover, addition of oleic acid, which tilted the balance towards elevated levels of MUFA, produced IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the biodistribution of lipids in the organelles of glioma, providing a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.</p><p><br></p><p>Linked studies;</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1967' rel='noopener noreferrer' target='_blank'>MTBLS1967</a> FA_HILICZ</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1974' rel='noopener noreferrer' target='_blank'>MTBLS1974</a> LCMS(CSHPos)</p>
2020-11-24 | MTBLS1973 | MetaboLights
Project description:<p>Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring an isocitrate dehydrogenase 1 mutation (IDHmut), acquire a different tumor biology and clinical manifestation than those that are IDHWT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we discovered monounsaturated (MUFA) to polyunsaturated (PUFA) lipid imbalances in organelles, generated by IDH mutation in cells and patient tissue, that were responsible for Golgi and ER dilation. We demonstrated a direct link between the IDH mutation and these organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate limiting enzyme in MUFA biosynthesis. Inhibition of IDH mutation or SCD silencing restored ER and Golgi morphology, while D-2HG and oleic acid induced morphological defects in these organelles. Moreover, addition of oleic acid, which tilted the balance towards elevated levels of MUFA, produced IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the biodistribution of lipids in the organelles of glioma, providing a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.</p><p><br></p><p>Linked studies;</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1967' rel='noopener noreferrer' target='_blank'>MTBLS1967</a> FA_HILICZ</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1973' rel='noopener noreferrer' target='_blank'>MTBLS1973</a> LCMS(CSHNeg)</p>
2020-11-24 | MTBLS1974 | MetaboLights