Pan-HDAC Inhibition Reverses the Warburg Effect and Leads to Metabolic Vulnerabilities
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE124877 | GEO | 2020/03/24
REPOSITORIES: GEO
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Project description:Pan-HDAC Inhibition Reverses the Warburg Effect and Leads to Metabolic Vulnerabilities
| PRJNA514055 | ENA
Project description:Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies.
| S-EPMC8410792 | biostudies-literature
Project description:Overcoming resistance to chemotherapies remains a major unmet need for cancers such as triple negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-Oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclearknown. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-CoA. Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.
2022-05-31 | GSE201051 | GEO
Project description:Overcoming resistance to chemotherapies remains a major unmet need for cancers such as triple negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-Oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclearknown. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-CoA. Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.
2022-05-31 | GSE201052 | GEO
Project description:Extrinsic skin ageing converges on the dermis, a post-mitotic tissue compartment consisting of extracellular matrix and long-lived fibroblasts prone to damage accumulation and maladaptation. Aged human fibroblasts exhibit mitochondrial and nuclear dysfunctions, which may be a cause or consequence of ageing. We report on a systematic study of human dermal fibroblasts retrieved from female donors aged 20-67years and analysed ex vivo at low population doubling precluding replicative senescence. According to gene set enrichment analysis of genome wide array data, the most prominent age-associated change of the transcriptome was decreased expression of mitochondrial genes. Consistent with that, mitochondrial content and cell proliferation declined with donor age. This was associated with upregulation of AMP-dependent protein kinase (AMPK), increased mRNA levels of PPARγ-coactivator 1α (PGC1A) and decreased levels of NAD(+)-dependent deacetylase sirtuin 1. In the old cells the PGC1A-mediated mito-biogenetic response to direct AMPK-stimulation by AICAR was undiminished, while the PGC1A-independent mito-biogenetic response to starvation was attenuated and accompanied by increased ROS-production. In summary, these observations suggest an age-associated decline in PGC1A-independent mito-biogenesis, which is insufficiently compensated by upregulation of the AMPK/PGC1A-axis leading under baseline conditions to decreased mitochondrial content and reductive overload of residual respiratory capacity.
2014-04-08 | GSE55118 | GEO
Project description:Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.
2024-03-12 | GSE236733 | GEO
Project description:Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.
2024-03-12 | GSE236724 | GEO
Project description:A mitochondrial long-chain fatty acid oxidation defect leads to dysregulation of plasma long-chain acyl carnitines, dysregulation of plasma amino acids, and an increased reliance on glucocorticoid signaling to maintain euglycemia during fasting. [muscle] Skeletal muscle tissue relies on products of fatty acid oxidation (FAO) during conditions of metabolic stress: fasting, prolonged exercise, febrile illness. Fasting-induced hypoglycemia and rhabdomyolysis are characteristic features of FAO disorders including very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD). However, the pathophysiological mechanisms that underlie the connection between FAO dysfunction and skeletal muscle dysfunction are not known. Here, we investigated the transcriptional response in skeletal muscle tissue (gastrocnemius) to the FAO defect in a model of VLCADD: the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse. We found that differentially expressed genes in the muscle were associated with molecular networks annotated for the cellular response to starvation from population-based models. To validate the association between the starvation response and FAO, we pharmacologically inhibited both glucocorticoid signaling and FAO in a model of fasting and observed that mice depleted in both pathways lost less weight during fasting and became hypoglycemic. These findings implicate glucocorticoid signaling as a candidate modifier of the cellular response to starvation in muscle tissue in the context of FAO disorders including VLCADD.
2024-10-26 | GSE186648 | GEO
Project description:<p>Overcoming resistance to chemotherapies remains a major unmet need for cancers such as triple negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-Oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-CoA. Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.</p>
2022-05-31 | MTBLS4709 | MetaboLights
Project description:Cancer cells exhibit an aberrant metabolism which facilitates more efficient production of biomass, and hence tumor growth and progression. The genetic cues modulating this metabolic switch remain largely undetermined, however. Here we identify a metabolic function for PML which reveals an unexpected role for this bona-fide tumor suppressor in pro-survival activity in breast cancer. We find that PML acts as both a negative regulator of PGC1A acetylation and as a potent activator of peroxisome proliferator-activated receptor (PPAR) signaling and fatty acid oxidation (FAO). We further show that as FAO PML promotes ATP production, inhibits anoikis, and allows luminal filling in 3D basement membrane breast culture models. Furthermore, analysis of breast cancer biopsies reveals that PML is over-expressed in a subset of breast cancers, and is enriched in triple-negative cases. Indeed, PML expression in breast cancer correlates strikingly with reduced time to recurrence, a gene signature of poor prognosis and activated PPAR signaling. These findings have important therapeutic implications, as PML and its key role in FAO metabolism are amenable to pharmacological suppression as a mode of cancer prevention and treatment. Mouse livers from Pml-WT and Pml-KO mice were harvested after 20 week diet with high fat diet (60% Cal from fat; Harlan 06414) or control diet (10% Cal from fat; Harlan 08806). Mice were fasted for 8h prior to tissue harvesting in order to avoid the effect of immediate food intake. 3 tissue extracts per genotype and condition were analyzed (out of a total of 8 mice per group).
2013-01-29 | E-GEOD-39220 | biostudies-arrayexpress