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Hypoxia promotes histone H3K9 lactylation to enhance LAMC2 transcription in esophageal squamous cell carcinoma

ABSTRACT: Hypoxia promotes histone H3K9 lactylation to enhance LAMC2 transcription in esophageal squamous cell carcinoma

PROVIDER: PRJNA1074731 | ENA |

REPOSITORIES: ENA

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Hypoxia promotes histone H3K9 lactylation to enhance LAMC2 transcription in esophageal squamous cell carcinoma

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

Hypoxia promotes histone H3K9 lactylation to enhance <i>LAMC2</i> transcription in esophageal squamous cell carcinoma.

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

Hypoxia promotes histone H3K9 lactylation to enhance LAMC2 transcription in esophageal squamous cell carcinoma

Project description:To identify potential histone Kla sites trigged by hypoxia in ESCC, we performed a stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomic analysis coupled with Kla affinity enrichment to characterize the landscape of histone Kla in the KYSE30 cells

2024-01-29 | PXD048995 |

Identification of SIRT3 as an eraser for H3K9 lactylation by antibody-mediated proximity labeling strategy

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

OGD-Induced Lactylation of H3K9 Contributes to M1 polarization and Inflammation of microglia Through TNF pathway

Project description:Hypoxia-induced M1 polarization of microglia and the resultant inflammatory response are pivotal mechanisms in the development of hypoxic-ischemic encephalopathy (HIE). Recent studies have identified lactylation of histones as a novel epigenetic modification, in which lactate groups are added to lysine residues on histones. Lactate, a product of cellular respiration, accumulates in the cytoplasm when cells experience hypoxia due to the conversion of pyruvate by lactate dehydrogenase. Therefore, histone lactylation may be involved in the pathogenesis of HIE. This study aims to investigate the role and mechanism of histone lactylation in hypoxia-induced M1 polarization of microglia and the associated inflammation, with the goal of providing new insights for the research and treatment of HIE.

2024-10-30 | GSE272754 | GEO

Identification of SIRT3 as an eraser for H3K9 lactylation by antibody-mediated proximity labeling strategy

Project description:Identification of SIRT3 as an eraser for H3K9 lactylation by antibody-mediated proximity labeling strategy

| PRJNA1147570 | ENA

OGD-Induced Lactylation of H3K9 Contributes to M1 polarization and Inflammation of microglia Through TNF pathway

Project description:OGD-Induced Lactylation of H3K9 Contributes to M1 polarization and Inflammation of microglia Through TNF pathway

| PRJNA1138673 | ENA

Ikzf1 lactylation regulates CD4 T cell differentiation

Project description:Dysregulation of Th17 differentiation was implicated in multiple inflammatory and autoimmune diseases including autoimmune uveitis. In the current study, we have provided evidence indicating that lactate-derived lactylation plays important roles in regulating Th17 differentiation. The lactylation level of CD4+ T cells was upregulated in EAU mice and inhibiting lactylation resulted in impaired EAU progression. We characterized the global lactylome of CD4+ T cells of normal and EAU mice. We found that the differentially lactylated proteins were enriched in pathways related to immune responses including leukocyte differentiation. Importantly, our results show that the lactylation level of Ikzf1 (K164) functions in regulating Th17 differentiation by differentially modulating gene expression patterns which are related to CD4+ T cell differentiation by CUT& Tag analysis. In view of the above mentioned well-documented evidence, Ikzf1 lactylation might represent an important regulator for Th17 differentiation in autoimmune uveitis.

2023-08-28 | GSE226678 | GEO

Tumor-associated macrophage derived lactate remodeling glioblastoma stem cells immune microenvironment through lactylation in glioblastoma

Project description:Glioblastoma (GBM) is a malignancy with the complex tumor microenvironment (TME) dominated by glioblastoma stem cells (GSCs) and infiltrated with tumor-associated macrophages (TAMs), exhibiting aberrant metabolism progress. Lactate is a critical glycolytic metabolite that promotes tumor progression. However, the mechanism of lactate transporting and lactylation in the tumor microenvironment (TME) of GBM remains elusive. Examination of lactate metabolic signature highly expressed on TAMs and tumor cells. We uncovered that TAMs provide lactate to GSCs, promoting GSCs proliferation and inducing the non-homologous end joining (NHEJ) protein KU70 lactylated at K317. Furthermore, TAM-derived lactate-inducing KU70 lactylation inhibits cGAS- type I interferon signaling, remodeling the immunosuppressive microenvironment through reduced cytotoxic CD8+ T cell infiltration, promoting the malignant progress of GBM. This study unveils TAMs-derived lactate and lactylation as a critical regulator of NHEJ, providing fresh insights into how aberrant lactylation and TME reprogramming are linked to DNA damage repair, which contributes to exploring new therapeutic strategies for targeting lactate transporters in combination with anti-PD-1-antibody to enhance anti-tumor immunity, which provides the theoretical basis for improving the clinical prognosis of GBM.

2024-06-01 | GSE266884 | GEO

Global Proteomic Analysis of Lysine lactylation in HMC3 cells under Normoxia or Hypoxia

Project description:This project carried out a quantitative study of lactylation in HMC3 Cell Line. In order to ensure a high degree of credibility of the results, we used the standard of localization probability>0.75 to filter the authentication data. In this study, a total of 3093 lactylation sites located on 1270 proteins were identified, of which 1601 sites of 751 proteins contain quantitative information. Subsequently, we carried out a systematic bioinformatics analysis of proteins containing quantitative information sites, including protein annotation, functional classification, functional enrichment and cluster analysis based on functional enrichment.

2023-03-28 | PXD028737 | Pride

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