Hypoxia promotes histone H3K9 lactylation to enhance LAMC2 transcription in esophageal squamous cell carcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Kai Zhang
PROVIDER: PXD048995 | iProX | Mon Jan 29 00:00:00 GMT 2024
REPOSITORIES: iProX
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Project description:Hypoxia promotes tumorigenesis and lactate accumulation in esophageal squamous cell carcinoma (ESCC). Lactate can induce histone lysine lactylation (Kla, a recently-identified histone marks) to regulate transcription. However, the functional consequence of histone Kla under hypoxia in ESCC remains to be explored. Here, we reveal that hypoxia facilitates histone H3K9la to enhance LAMC2 transcription for proliferation of ESCC. We found that global level of Kla was elevated under hypoxia, and thus identified the landscape of histone Kla in ESCC by quantitative proteomics. Furthermore, we show a significant increase of H3K9la level induced by hypoxia. Next, MNseq ChIP-seq and RNA-seq analysis suggest that H3K9la is enriched at the promoter of cell junction genes. Finally, we demonstrate that the histone H3K9la facilitates the expression of LAMC2 for ESCC invasion by in vivo and in vitro experiments. Briefly, our study reveal a vital role of histone Kla triggered by hypoxia in cancer.
2024-05-22 | GSE255352 | GEO
Project description:As a novel post-translational modification of histone derived from lactate, lysine lactylation (Kla) links lactate metabolism to epigenetic regulation, playing a role in modulation of gene expression in tumor and immune microenvironment. Evidence so far indicates that HDAC1-3 can catalyze the removal of Kla. However, the regulated targets of HDACs for Kla and functional consequence remain elusive. Herein, we used an antibody-based proximity labeling approach to identify SIRT3 binding to histone H3K9la and catalytic removal of the lactylationoup. The molecular docking results further revealed the mechanism of the binding of Kla peptide to SIRT3. More importantly, SIRT3 can specifically modulate the gene transcription by regulating H3K9la, inhibiting the progression of esophageal cancer cells (ESCC). In conclusion, our work identifies the delactylase of H3K9la and reveal an H3K9la-mediated molecular mechanism catalyzed by SIRT3 for gene transcription regulation in ESCC, and our findings provide an opportunity to investigate the physiological significance of Kla and shed light on the unknown cellular mechanisms controlled by SIRT3.
2025-02-24 | PXD054857 | Pride
Project description:Hypoxia promotes tumorigenesis and lactate accumulation in esophageal squamous cell carcinoma (ESCC). Lactate can induce histone lysine lactylation (Kla, a recently identified histone marks) to regulate transcription. However, the functional consequence of histone Kla under hypoxia in ESCC remains to be explored. Here, we reveal that hypoxia facilitates histone H3K9la to enhance LAMC2 transcription for proliferation of ESCC. We found that global level of Kla was elevated under hypoxia, and thus identified the landscape of histone Kla in ESCC by quantitative proteomics. Furthermore, we show a significant increase of H3K9la level induced by hypoxia. Next, MNase ChIP-seq and RNA-seq analysis suggest that H3K9la is enriched at the promoter of cell junction genes. Finally, we demonstrate that the histone H3K9la facilitates the expression of LAMC2 for ESCC invasion by in vivo and in vitro experiments. Briefly, our study reveals a vital role of histone Kla triggered by hypoxia in cancer.
| S-EPMC11233973 | biostudies-literature
Project description:As a novel post-translational modification of histone derived from lactate, lysine lactylation (Kla) links lactate metabolism to epigenetic regulation, playing a role in modulation of gene expression in tumor and immune microenvironment. Evidence so far indicates that HDAC1-3 can catalyze the removal of Kla. However, the regulated targets of HDACs for Kla and functional consequence remain elusive. Herein, we used an antibody-based proximity labeling approach to identify SIRT3 binding to histone H3K9la and catalytic removal of the lactylationoup. The molecular docking results further revealed the mechanism of the binding of Kla peptide to SIRT3. More importantly, SIRT3 can specifically modulate the gene transcription by regulating H3K9la, inhibiting the progression of esophageal cancer cells (ESCC). In conclusion, our work identifies the delactylase of H3K9la and reveal an H3K9la-mediated molecular mechanism catalyzed by SIRT3 for gene transcription regulation in ESCC, and our findings provide an opportunity to investigate the physiological significance of Kla and shed light on the unknown cellular mechanisms controlled by SIRT3.
2025-02-27 | PXD061251 |
Project description:Dysregulation of histone acetylation is widely implicated in tumorigenesis, yet its specific roles in the progression and metastasis of esophageal squamous cell carcinoma (ESCC) remains unclear. We here profiled the genome-wide landscape of H3K9ac for paired adjacent normal (Nor), primary ESCC (EC) and metastatic lymph node (LNC) esophageal tissues from three ESCC patients. By integrating these data with the corresponding H3K27ac profiles, we identified a distinct epigenetic reprogramming specific to H3K9ac in EC and LNC samples compared to Nor samples, which predominantly targeted genes functionally associated with tumorigenesis and metastasis, and contributed to their transcriptomic aberrations. The findings were further verified by a publicy available single cell RNA-seq data and in vitro experiment, highlighting the potential therapeutic avenues for intervening ESCC through epigenetic modulation via H3K9ac.
2023-06-08 | GSE234346 | GEO
Project description:We have identified a new histone modification, which is derived from glycolysis end product, lactate. By SILAC-MS/MS based quantification, and U-13C6 glucose labeling experiments, we demonstrate that histone Kla is regulated by cellular glycolysis pathway
2019-08-01 | PXD014870 | Pride
Project description:As a novel post-translational modification of histone derived from lactate, lysine lactylation (Kla) links lactate metabolism to epigenetic regulation, playing a role in modulation of gene expression in tumor and immune microenvironment. Evidence so far indicates that HDAC1-3 can catalyze the removal of Kla. However, the regulated targets of HDACs for Kla and functional consequence remain elusive. Herein, we used an antibody-based proximity labeling approach to identify SIRT3 binding to histone H3K9la and catalytic removal of the lactylationoup. The molecular docking results further revealed the mechanism of the binding of Kla peptide to SIRT3. More importantly, SIRT3 can specifically modulate the gene transcription by regulating H3K9la, inhibiting the progression of esophageal cancer cells (ESCC). In conclusion, our work identifies the delactylase of H3K9la and reveal an H3K9la-mediated molecular mechanism catalyzed by SIRT3 for gene transcription regulation in ESCC, and our findings provide an opportunity to investigate the physiological significance of Kla and shed light on the unknown cellular mechanisms controlled by SIRT3.
2024-08-18 | GSE274648 | GEO
Project description:SOX2 is not only a pioneer transcription factor with critical roles in stem cell function and cell reprogramming but also a potent initiating oncodriver for a multitude of squamous cancers. How SOX2 exerts a potent oncogenic activity in squamous lineage is largely unknown. Here we uncovered a unique role of SOX2 in driving up global histone acetylation in various esophageal squamous cancer cells (ESCCs). Chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated that knockdown of SOX2 in ESCC cells resulted in a global down-regulation of histone acetylation and impaired about half of the super-enhancers. We engineered an ESCC SOX2-dTAG cell line that allowed rapid degradation of SOX2, and subsequent ChIP-seq confirmed a role of SOX2 in promoting global histone acetylation, beside its role in promoting local histone acetylation at SOX2 binding regions. Combined metabolic and transcriptional analyses revealed two mechanisms by which SOX2 drives up global histone acetylation in ESCCs: promoting the expression of a panel of histone acetyltransferases and reducing long chain fatty acid synthesis/elongation at least in part by repressing the expression of long-chain acyl-CoA synthase 5 (ACSL5), which in turn channels acetyl-CoA to histone acetylation. We demonstrated that ACSL5 knockdown downregulated fatty acid synthesis/elongation and enhanced histone acetylation, whereas overexpression of ACSL5 resulted in lipid accumulation, histone hypoacetylation, and tumor growth inhibition. Finally, we showed that SOX2 expression correlates negatively with ACSL5 and positively with histone acetylation in clinical esophageal squamous tumors. Altogether, our study uncovers a role of SOX2 in reprogramming lipid metabolism and driving histone hyperacetylation and super-enhancer function, providing new mechanistic insights of SOX2 acting as a potent oncodriver.
2025-07-21 | GSE300317 | GEO
Project description:The high recurrence rate and poor survival prospects of esophageal squamous cell carcinoma (ESCC) patients after treatment make the ongoing research on chemoprevention drugs for ESCC particularly important. In helping to solve this problem, we screened a large number of FDA-approved drugs and found that levodopa, a drug used to treat Parkinson’s disease, has an inhibitory effect on the growth of ESCC cells. To elucidate the molecular mechanisms, we applied mass spectrometry to investigate the anti-tumor activity of levodopa on ESCC. The results suggest that levodopa can down-regulate oxidative phosphorylation, non-alcoholic fatty liver disease (NAFLD) and parkinson disease pathways. SDHD, NDUFS4 and MT-CO3, major respiratory compounds in the mitochondria, were involved in these pathways. Down-regulation of these proteins is associated with mitochondrial dysfunction. Western blotting and immunofluorescence results confirmed the authenticity of proteomics data. Cell viability assay revealed that mitochondrial activity had been suppressed after levodopa treatment. Mitochondrial membrane potential reduction was detected by JC-1 and TMRE assays. And transmission electron microscope (TEM) analysis indicated that mitochondrial morphology changed. Taken together, levodopa inhibits the growth of ESCC through restraining the mitochondria.
2021-09-08 | PXD013824 | Pride
Project description:Esophageal squamous cell carcinoma (ESCC) is a heterogeneous cancer associated with high mortality rate. In India, it is the 6th most common cause of cancer-related mortality. In this study, we employed high-resolution mass spectrometry-based quantitative proteomics to characterize differential protein expression pattern associated with ESCC. We identified several differentially expressed proteins including PDPN, TOP2A, POSTN and MMP2 that were overexpressed in ESCC. In addition, we identified downregulation of esophagus tissue-enriched proteins such as SLURP1, PADI1, CSTA and small proline-rich proteins like SPRR3, SPRR2A, SPRR1A and CSTA, KRT4, KRT13 involved in squamous cell differentiation. We identified several overexpressed proteins belonging to 3q24-29 chromosomal region, corroborating CNV alterations in this region reported by several published studies. For example, we identified overexpression of SOX2, TP63, IGF2BP2 and RNF13 that are encoded by 3q26 region. Functional enrichment analysis revealed proteins involved in cell cycle pathways, DNA replication, spliceosome, and DNA repair pathways. We identified overexpression of multiple proteins that play a major role in alleviating ER stress. SYVN1/SEL1L complex forms the ER quality control machinery clearing misfolded proteins from ER. SYVN1 is an E3 ubiquitin ligase that ubiquitinates ER-resident proteins. There are also other non-canonical substrates of SYVN1 which are known to play a crucial role in tumor progression. Therefore, SYVN1 is a potential therapeutic target in ESCC.
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