SDHA/B reduction promotes hepatocellular carcinoma proliferation by removing cullin1 NEDDylation and stabilizing YAP/TAZ
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA853924 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19894956_1.fastq.gz | Fastqsanger.gz | |||
| SRR19894956_2.fastq.gz | Fastqsanger.gz | |||
| SRR19894957_1.fastq.gz | Fastqsanger.gz | |||
| SRR19894957_2.fastq.gz | Fastqsanger.gz | |||
| SRR19894958_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Background & Aims: Succinate dehydrogenase enzyme (SDH) is frequently found to be diminished in Hepatocellular carcinoma (HCC) patient samples, and SDH reduction is associated with elevated succinate level and poor prognosis in HCC patients. But the underlying mechanisms about how impaired SDH activity promotes HCC malignancy remain unclear. Approach & Results: In this study, we observed remarkable downregulations of SDH subunits A and B (SDHA/B) in chronic liver injury-induced murine HCC models and HCC patient samples. Subsequent RNA sequencing, hematoxylin & eosin (H&E) staining and immunohistochemistry (IHC) analyses of HCC samples revealed that Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) were significantly upregulated in HCC, with their levels inversely correlating with that of SDHA/B. The protein stability of YAP/TAZ was greatly enhanced in SDHA/B-depleted HCC cells along with accumulation of succinate. Further mechanistic analyses demonstrated that impaired activity of SDHA/B resulted in succinate accumulation which facilitated the removal of NEDDylation on cullin1, therefore disrupted the E3 ubiquitin ligase SCFβ-TrCP complex, consequently led to YAP/TAZ stabilization and activation in HCC cells. The accelerated in vitro cell proliferation and in vivo tumor growth caused by SDHA/B reduction or succinate exposure were largely dependent on the aberrant activation of YAP/TAZ. Conclusions: Our study demonstrated that SDHA/B reduction promotes HCC proliferation by preventing the proteasomal degradation of YAP/TAZ through modulating cullin1 NEDDylation, thus addicts SDH-deficient HCC cells to YAP/TAZ pathway and renders these cells vulnerable to YAP/TAZ inhibition. Our findings warrant further investigation on the therapeutic effects of targeting YAP/TAZ in HCC patients displaying reduced SDHA/B or elevated succinate levels.
2023-05-31 | GSE207147 | GEO
Project description:The microarray study was used to compare the gene expression profile of EDL933 in LB, sdhA deletion mutant in LB, and sdhA deletion mutant in LB with 2.5 mM Fumaric acid.
2017-07-01 | GSE86632 | GEO
Project description:As women age, their oocytes decline in both quantity and quality, leading to eventual infertility. Part of this decline is associated with increased levels of reactive oxygen species and decreased mitochondrial function, which are associated with lower live birth rates. However, detailed mechanisms regulating mitochondrial function and mitochondrial decline in aged oocytes are unknown. Here we show that NEDDylation, a protein posttranslational modification, modulates mitochondrial transcription in oocytes to maintain quality over time. In this proteomic study we compared NEDDylation pathway, UBA3, knockout oocytes to control oocytes to investigate proteomic changes due to loss of NEDD8 conjugation.
2026-05-06 | PXD076100 | Pride
Project description:Mitochondrial dysfunction and redox imbalance are key drivers of metabolic dysfunction-associated steatohepatitis (MASH), yet therapeutic strategies targeting mitochondrial respiratory integrity remain limited. We identified succinate dehydrogenase subunit A (SDHA) as a direct functional target of the natural limonoid compound DDK. Using CETSA coupled with mass spectrometry (MS) and bio-layer interferometry (BLI), we demonstrate that DDK directly binds SDHA. The mitochondrial-protecting and oxidative phosphorylation (OXPHOS)-recovering effects of limonoid compound DDK were abolished in SDHA-deficient hepatocytes, suggesting that SDHA is indispensable for DDK’s bioactivity. SDH activity decreased in the liver tissues of MASH murine models, while SDHA knockdown in hepatocytes further aggravated impaired OXPHOS activity and mitochondrial dysfunction. Mechanistically, DDK promoted complex II (SDH) assembly and enzymatic activity by reducing pathological acetylation of SDHA at lysine 335. Site-specific mutation of K335 abrogated DDK-induced enhancement of complex II assembly and mitochondrial respiration, demonstrating that SDHA deacetylation is required for its therapeutic efficacy. To conclude, our findings uncover an SDHA acetylation–complex II assembly axis as a therapeutic strategy in MASH, offering evidence that DDK may be a new therapeutic option for MASH treatment.
2026-05-01 | GSE325089 | GEO
Project description:This dataset contains mass spectrometry data for O-GlcNAc site identification on SDHA. The data were generated to identify and characterize O-GlcNAc modification sites on the SDHA protein.
| PXD078261 |
Project description:Cell growth and survival depend on a delicate balance between energy production and synthesis of metabolites. We have discovered that an alternative mitochondrial complex II (CII) assembly, designated here as CIIlow, serves as a check-point for metabolite biosynthesis under bioenergetic stress, with cells suppressing their energy utilization by modulating DNA synthesis and cell cycle progression. Depletion of CIIlow leads to an imbalance in energy utilization and metabolite synthesis, as evidenced by recovery of the de novo pyrimidine pathway and unlocking cell cycle arrest from the S-phase. In vitro experiments are further corroborated by analysis of paraganglioma tissues from patients with sporadic, SDHA and SDHB mutations. These findings uncover a new core complex inside mitochondria that provides homeostatic control of cellular metabolism to reflect availability of energy, with SDHA being its central molecule.
2018-04-16 | GSE108938 | GEO
Project description:Myelination is essential for neuronal function and health. In peripheral nerves, >100 causative mutations have been identified that cause Charcot-Marie-Tooth disease, a disorder that can affect myelin sheaths. Among these, a number of mutations are related to essential targets of the post-translation modification neddylation, although how these lead to myelin defects is unclear. Here, we demonstrate that inhibiting neddylation leads to a striking absence of peripheral myelin and axonal loss both in developing and regenerating mouse nerves. Importantly, our data indicate that neddylation exerts a global influence on the complex transcriptional and post-transcriptional program by simultaneously regulating the expression and function of multiple essential myelination signals, including the master transcription factor EGR2 and the negative regulators c-Jun and Sox2, and inducing global secondary changes in downstream pathways, including the mTOR and YAP/TAZ signalling pathways. This places neddylation as a critical regulator of myelination and delineates the potential pathogenic mechanisms involved in CMT mutations related to neddylation.
2024-03-06 | GSE241269 | GEO
Project description:BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR-ABL1-targeting TKIs in CML. Unlike their function in reducing drug resistance in many solid tumors, we revealed that neddylation inhibitors counteracted the cytotoxicity of TKIs against CML cells, both in cellular experiments and in animal model. Conversely, neddylation agonist sensitized the function of TKIs. RNA sequencing data revealed that neddylation inhibitor reversed the transcriptomic changes induced by TKI. Co-immunoprecipitation (co-IP) assay identified ABL1 kinase domain as a novel substrate for neddylation. Furthermore, an artificial intelligence (AI) 3-Dimensional spatial structure binding technology was employed to predict the impact of neddylation on the structure of ABL1 kinase domain. Finally, we provided potential evidence showing that TKI therapy decreased the expression of neddylation enzymes in the bone marrow of CML patients. Hence, our study offers new insights into the post-translational modification (PTM)-mediated drug resistance, and highlights the potential clinical benefits of neddylation agonists in improving the responsiveness of BCR-ABL1 TKIs in CML.
2024-09-15 | GSE275701 | GEO
Project description:We used microarrays to detail the global program of gene expression underlying SAG-dependent neddylation and identified distinct classes of disparate genes during this process.
2020-03-31 | GSE83593 | GEO
Project description:Age-related cardiac dysfunction is closely linked to impaired mitophagy and mitochondrial quality control. Here, we identify neddylation inhibition as a previously unrecognized strategy to activate mitophagy and improve cardiac function during aging. Using high-content screening of ~10,000 compounds, we uncovered MLN4924, a clinically advanced neddylation inhibitor, as a potent inducer of mitophagy across diverse systems. MLN4924 enhanced mitophagic flux in human iPSC-derived cardiomyocytes and mouse hearts via a non-canonical pathway that bypasses PINK1/Parkin and mitochondrial fission. Mechanistically, MLN4924 stabilized HIF1α by disrupting CUL2-mediated degradation, leading to upregulation of the mitophagy receptor BNIP3. In aged mice, late-life MLN4924 treatment restored cardiac mitophagy, reversed ventricular hypertrophy, and improved diastolic function. MLN4924 also extended lifespan in C. elegans, underscoring the systemic benefit of neddylation blockade. These findings establish neddylation as a druggable regulator of mitochondrial quality control and aging, offering a potential therapeutic framework to combat age-related cardiac decline.
2026-02-01 | GSE317599 | GEO