Cytoplasmic localization of SETDB1 induced Warburg effect via c-MYC/ LDHA axis to enhance migration and invasion in breast carcinoma
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ABSTRACT:
PROVIDER: PRJNA1066816 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27663385.fastq.gz | Fastqsanger.gz | |||
| SRR27663386.fastq.gz | Fastqsanger.gz | |||
| SRR27663387.fastq.gz | Fastqsanger.gz | |||
| SRR27663388.fastq.gz | Fastqsanger.gz | |||
| SRR27663389.fastq.gz | Fastqsanger.gz |
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Project description:SETDB1, a pivotal histone lysine methyltransferase, has been identified as being transported to the cytoplasm through a CMR1-dependent pathway, contributing to non-histone methylation. However, the function and underlying mechanism of cytoplasmic SETDB1 in breast cancer remain elusive. This study, employing immunohistochemistry, revealed that an elevated level of cytoplasmic SETDB1 is correlated with lymph node metastasis and more aggressive breast cancer subtypes. Functionally, cytoplasmic SETDB1 proves indispensable for cell migration and invasion, as well as the induction of epithelial-mesenchymal transition (EMT), which could be reversed by LMB (a CMR1 inhibitor) treatment. Furthermore, it was observed that cytoplasmic SETDB1 elevates the levels of metabolites associated with the Warburg effect, including glucose, pyruvate, lactate, and ATP. Mechanistically, the release of nuclear SETDB1 alleviates the inhibition of c-MYC transcription, leading to increased c-MYC expression and subsequent up-regulation of LDHA expression. Notably, LDHA overexpression enhanced migration and invasion by inducing EMT, while its depletion can reverse SETDB1-induced migration and invasion, as well as the Warburg effect and EMT. In conclusion, the subcellular localization of cytoplasmic SETDB1 emerges as a pivotal factor in breast cancer progression. This study offers valuable insights into the novel functions and mechanisms of cytoplasmic SETDB1.
2024-03-13 | GSE253717 | GEO
Project description:SET domain bifurcated 1 (SETDB1), a pivotal histone lysine methyltransferase, is transported to the cytoplasm via a chromosome region maintenance 1 (CMR1)‑dependent pathway, contributing to non‑histone methylation. However, the function and underlying mechanism of cytoplasmic SETDB1 in breast cancer remain elusive. In the present study, immunohistochemistry revealed that elevated cytoplasmic SETDB1 was correlated with lymph node metastasis and more aggressive breast cancer subtypes. Functionally, wound healing and Transwell assays showed that cytoplasmic SETDB1 is key for cell migration and invasion, as well as induction of epithelial‑mesenchymal transition (EMT), which was reversed by leptomycin B (LMB, a CMR1 inhibitor) treatment. Furthermore, RNA‑seq and metabolite detection revealed that cytoplasmic SETDB1 was associated with metabolism pathway and elevated levels of metabolites involved in the Warburg effect, including glucose, pyruvate, lactate and ATP. Immunoblotting and reverse transcription‑quantitative PCR verified that elevation of cytoplasmic SETDB1 contributed to elevation of c‑MYC expression and subsequent upregulation of lactate dehydrogenase A (LDHA) expression. Notably, gain‑ and loss‑of‑function approaches revealed that LDHA overexpression in T47D cells enhanced migration and invasion by inducing EMT, while its depletion in SETDB1‑overexpressing MCF7 cells reversed SETDB1‑induced migration and invasion, as well as the Warburg effect and EMT. In conclusion, subcellular localization of cytoplasmic SETDB1 may be a pivotal factor in breast cancer progression. The present study offers valuable insight into the novel functions and mechanisms of cytoplasmic SETDB1.
| S-EPMC10914311 | biostudies-literature
Project description:NUSAP1-LDHA-Glycolysis-Lactate feedforward loop promotes Warburg effect and metastasis in pancreatic ductal adenocarcinoma
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Project description:NUSAP1-LDHA-Glycolysis-Lactate feedforward loop promotes Warburg effect and metastasis in pancreatic ductal adenocarcinoma [ChIP-seq]
| PRJNA902015 | ENA
Project description:The histone 3 lysine 9 (H3K9)-specific methyltransferase (KMT) Setdb1 is essential for both stem cell pluripotency and terminal differentiation of different cell types. To shed light on Setdb1 role(s) in these mutually exclusive processes, we used mouse skeletal myoblasts as a model of terminal differentiation. Ex vivo studies on isolated single myofibres showed that Setdb1 is required for muscle adult stem cells expansion following activation and in vitro studies on skeletal myoblasts confirmed that Setdb1 suppresses terminal myoblast differentiation. We used genome-wide analyses to identify Setdb1 direct target genes in myoblasts and observed a release of Setdb1 from the promoter of selected target genes upon myoblast terminal differentiation, concomitant to a nuclear export of Setdb1 to the cytoplasm. We demonstrated that both genomic release and cytoplasmic Setdb1 relocalisation during differentiation were dependent on canonical Wnt signalling. Taken together, our findings uncover a functional link between Setdb1 and canonical Wnt signalling in skeletal muscle cells, which affects the expression of a subset of Setdb1 target genes. We revealed Wnt-dependent subcellular relocalisation of Setdb1 as a novel mechanism regulating Setdb1 functions. ChIP-seq of Setdb1 and H3K9me3 in Myoblast cells (C2C12)
2016-02-01 | E-GEOD-65493 | biostudies-arrayexpress
Project description:LDHA is key enzyme for tumor glycolysis metabolism and knocking down LDHA would change a lot of gene expression We used microarrays to detail the global gene expression in 4T1 cells with LDHA knocked down by shRNA
2017-09-16 | GSE103925 | GEO
Project description:Altered glycolysis is the most fundamental metabolic change associated with the Warburg effect. However, the precise mechanisms are not completely understood. Here we dissect how MNX1-AS1 reinforces the Warburg effect through facilitating the non-glycolytic actions of PKM2 in the nucleus. We found that MNX1-AS1 expression was frequently overexpressed in hepatocellular carcinoma (HCC). In the context of HCC, we show MNX1-AS1 acts as a scaffold to promote interactions between PKM2 and importin α5. Upon EGFR activation, the resulting ternary complex drives the translocation of PKM2 into the nucleus. In consequence, glycolytic pathway components including key mediators of the Warburg effect (LDHA, Glut1 and PDK1) are upregulated. Manipulating MNX1-AS1 elicited robust effects on glycolysis associated with marked changes in HCC growth in vitro and in vivo, indicative of the significant contribution of MNX1-AS1 to tumorigenesis. Moreover, while MNX1-AS1 expression is driven by c-Myc, its actions associated with PKM2 were shown to be downstream and independent of c-Myc. Given the status of MNX1-AS1 as a pan-cancer upregulated lncRNA, this implicitly highlights the potential of targeting MNX1-AS1 to selectively counter the Warburg effect in a range of tumor types.
2022-11-23 | GSE213064 | GEO
Project description:Von Hippel-Lindau (VHL) is a tumor suppressor that functions as the substrate recognition subunit of the CRL2VHL E3 complex. While substrates of VHL have been identified, its tumor suppressive role remains to be fully understood. For further determination of VHL substrates, we analyzed the physical interactome of VHL and identified the histone H3K9 methyltransferase SETBD1 as a novel target. SETDB1 undergoes oxygen-dependent hydroxylation by prolyl hydroxylase domain proteins (PHD) and the CRL2VHL complex recognizes hydroxylated SETDB1 for ubiquitin-mediated degradation. Under hypoxic conditions, SETDB1 accumulates by escaping CRL2VHL activity. Loss of SETDB1 in hypoxia compared with that in normoxia escalates the production of transposable element (TE)-derived double-stranded RNAs (dsRNAs), thereby hyperactivating the immune-inflammatory response. In addition, strong derepression of TEs in hypoxic cells lacking SETDB1 triggers DNA damage-induced death. Our collective results support a molecular mechanism of oxygen-dependent SETDB1 degradation by the CRL2VHL E3 complex and reveal a role of SETDB1 in genome stability under hypoxia.
2024-01-26 | PXD037104 | Pride
Project description:The histone 3 lysine 9 methyltransferase Setdb1 is essential for both stem cell pluripotency and terminal differentiation of different cell types. To shed light on Setdb1 roles in these mutually exclusive processes, we used mouse skeletal myoblasts as a model of terminal differentiation. Ex vivo studies on isolated single myofibres showed that Setdb1 is required for adult muscle stem cells expansion following activation. In vitro studies in skeletal myoblasts confirmed that Setdb1 suppresses terminal differentiation. Genomic binding analyses showed a release of Setdb1 from selected target genes upon myoblast terminal differentiation, concomitant to a nuclear export of Setdb1 to the cytoplasm. Both genomic release and cytoplasmic Setdb1 relocalisation during differentiation were dependent on canonical Wnt signalling. Transcriptomic assays in myoblasts unravelled a significant overlap between Setdb1 and Wnt3a regulated genetic programs. Together, our findings revealed Wnt-dependent subcellular relocalisation of Setdb1 as a novel mechanism regulating Setdb1 functions and myogenesis. This SuperSeries is composed of the SubSeries listed below.
2016-02-01 | GSE70070 | GEO
Project description:The histone 3 lysine 9 methyltransferase Setdb1 is essential for both stem cell pluripotency and terminal differentiation of different cell types. To shed light on Setdb1 roles in these mutually exclusive processes, we used mouse skeletal myoblasts as a model of terminal differentiation. Ex vivo studies on isolated single myofibres showed that Setdb1 is required for muscle adult stem cells expansion following activation. In vitro studies in skeletal myoblasts confirmed that Setdb1 suppresses terminal myoblast differentiation. Genomic binding analyses showed a release of Setdb1 from the promoter of selected target genes upon myoblast terminal differentiation, concomitant to a nuclear export of Setdb1 to the cytoplasm. Both genomic release and cytoplasmic Setdb1 relocalisation during differentiation were dependent on canonical Wnt signalling. Together, our findings revealed Wnt-dependent subcellular relocalisation of Setdb1 as a novel mechanism regulating Setdb1 functions and adult myogenesis.
2016-02-01 | GSE70069 | GEO