Histon lactylation drives HAS2 expression in gastric cancer tumorigensis after H.pylori infection [ChIP-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE295142 | GEO | 2025/09/30
REPOSITORIES: GEO
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Project description:Histone lysine lactylation is a physiologically relevant epigenetic pathway that can be stimulated by the Warburg effect and hypoxia-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-CoA, the cofactor for the modification, and how this process is regulated remain unknown. Here, we report the identification of GTPSCS as a lactyl-CoA ligase using biochemistry and cell biology approaches. The mechanism of this catalytic activity was elucidated using the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to form a functional lactyltransferase to elevate histone H3 lysine 18 lactylation (H3K18la). This process is dependent on not only a nuclear localization signal in the GTPSCS G1 subunit but also acetylation at the G2 subunit residue K73 (for the interaction between GTPSCS and p300). GTPSCS-p300-mediated histone H3K18la promotes glioma cell proliferation and tumor formation in mice. In addition, histone H3K18la is positively associated with glioma grade and poor prognosis in glioma patients. The LDHA-GTPSCS-lactyltransferase-histone Kla axis thus represents a signal-stimulated epigenetic pathway that mediates the downstream impact of the Warburg effect and hypoxia
2024-12-04 | PXD037672 | Pride
Project description:After injury, muscles require fully functional macrophages to recover completely. During muscle regeneration, macrophages transition from a pro-inflammatory to a pro-restorative phenotype ensures the proper regeneration. Lactate is a crucial molecule for muscle-residing macrophage polarisation. Histone lactylation, a direct derivative of lactate, has been implicated in macrophage polarisation in vitro . In this work, we show for the first time that macrophages recruited to the muscle after ischemic injury modify their histone lactylome between 2 and 4 days post injury. Absolute histone lactylation levels increase significantly. Although subtly, also the genomic enrichment of H3K18la changes from 2 to 4 days post injury and this correlates with gene expression changes. Interestingly, we find that H3K18la genomic enrichment changes from day 2 to day 4 post injury are predictive for gene expression changes later in time, from day 4 to day 7, rather than being a reflection of past gene expression changes from day 1 to day 2. Our results suggest that histone lactylation dynamics are functionally important for the resolving action of macrophages during muscle regeneration.
2024-04-08 | GSE254129 | GEO
Project description:After injury, muscles require fully functional macrophages to recover completely. During muscle regeneration, macrophages transition from a pro-inflammatory to a pro-restorative phenotype ensures the proper regeneration. Lactate is a crucial molecule for muscle-residing macrophage polarisation. Histone lactylation, a direct derivative of lactate, has been implicated in macrophage polarisation in vitro . In this work, we show for the first time that macrophages recruited to the muscle after ischemic injury modify their histone lactylome between 2 and 4 days post injury. Absolute histone lactylation levels increase significantly. Although subtly, also the genomic enrichment of H3K18la changes from 2 to 4 days post injury and this correlates with gene expression changes. Interestingly, we find that H3K18la genomic enrichment changes from day 2 to day 4 post injury are predictive for gene expression changes later in time, from day 4 to day 7, rather than being a reflection of past gene expression changes from day 1 to day 2. Our results suggest that histone lactylation dynamics are functionally important for the resolving action of macrophages during muscle regeneration.
2024-04-08 | GSE254128 | GEO
Project description:Tumor cells are known for excessive lactate production, due to Warburg effect, and transcriptional dysregulation. However, how lactate influences the epigenetic modifications at a genome-wide level and its impact on gene transcription in tumor cell remains unclear. Addressing this gap, we analyzed genome-wide modification of H3K18 lactylation (H3K18la) in T-cell acute lymphoblastic leukemia (T-ALL). Integrated analysis with histone modifications with established functions show the H3K18la is mainly involved in active regulation of gene transcription. We report increased lactate and H3K18la modification levels in T-ALL as compared to normal T cells. We observe clusters of H3K18la modifications in patterns reminiscent of super-enhancers. We show a notable shift of genome-wide H3K18la modification from T cell immunity in normal T cells to leukemogenesis in T-ALL, correlating with altered gene transcription profiles. By disrupting H3K18la modification, we uncover both synergetic and divergent changes between H3K18la and H3K27ac modifications, suggesting the H3K18la and H3K27ac modifications may have specific regulation mechanisms correspondingly. These findings expand our understanding of metabolic disruptions involvement in transcription dysregulation through epigenetic changes in T-ALL, and emphasize the collective importance of histone modifications in maintaining oncogenic epigenetic stability.
2024-05-31 | GSE263584 | GEO
Project description:Tumor cells are known for excessive lactate production, due to Warburg effect, and transcriptional dysregulation. However, how lactate influences the epigenetic modifications at a genome-wide level and its impact on gene transcription in tumor cell remains unclear. Addressing this gap, we analyzed genome-wide modification of H3K18 lactylation (H3K18la) in T-cell acute lymphoblastic leukemia (T-ALL). Integrated analysis with histone modifications with established functions show the H3K18la is mainly involved in active regulation of gene transcription. We report increased lactate and H3K18la modification levels in T-ALL as compared to normal T cells. We observe clusters of H3K18la modifications in patterns reminiscent of super-enhancers. We show a notable shift of genome-wide H3K18la modification from T cell immunity in normal T cells to leukemogenesis in T-ALL, correlating with altered gene transcription profiles. By disrupting H3K18la modification, we uncover both synergetic and divergent changes between H3K18la and H3K27ac modifications, suggesting the H3K18la and H3K27ac modifications may have specific regulation mechanisms correspondingly. These findings expand our understanding of metabolic disruptions involvement in transcription dysregulation through epigenetic changes in T-ALL, and emphasize the collective importance of histone modifications in maintaining oncogenic epigenetic stability.
2024-05-20 | GSE263697 | GEO
Project description:Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate. Highly glycolytic proliferating cells such as cancer cells take advantage of HK2 expression to accelerate glucose metabolism even in the presence of oxygen. This acceleration not only provides sufficient glycolytic intermediates to support the anabolic demands of the cells but also inevitably accompanies increased formation of metabolic end products such as lactate. Currently, the effect of lactate caused by HK2-mediated metabolic alteration is largely unknown. A recent study found that lactate plays a role in an epigenetic alteration known as histone lactylation. Here, using RNA-seq and CUT&Tag chromatin profiling, we study the effect of HK2 and lactate on gene expression via histone lactylation (H3K18la).
2023-05-05 | GSE229153 | GEO
Project description:Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate. Highly glycolytic proliferating cells such as cancer cells take advantage of HK2 expression to accelerate glucose metabolism even in the presence of oxygen. This acceleration not only provides sufficient glycolytic intermediates to support the anabolic demands of the cells but also inevitably accompanies increased formation of metabolic end products such as lactate. Currently, the effect of lactate caused by HK2-mediated metabolic alteration is largely unknown. A recent study found that lactate plays a role in an epigenetic alteration known as histone lactylation. Here, using RNA-seq and CUT&Tag chromatin profiling, we study the effect of HK2 and lactate on gene expression via histone lactylation (H3K18la).
2023-05-05 | GSE229151 | GEO
Project description:Insufficient microwave ablation (IMWA) is linked to aggressive hepatocellular carcinoma (HCC) progression. An increase in lactate level after sublethal heat stress (HS) has been confirmed in HCC. However, the role of lactate-related histone lactylation in the progression of HCC underwent sublethal HS remains unclear. Here, we found that the metastatic potential of HCC is enhanced in a lactate-dependent manner after IMWA. Meanwhile, sublethal HS triggers an upregulation of H3K18la modification, as validated in a cell-derived xenograft mouse model and human HCC samples. By employing an integration analysis of proteomic and transcriptomic profiling, we revealed that HCC cells exhibit an upregulation of intracellular iron ion homeostasis and develop resistance to platinum-based drugs after exposure to sublethal HS. We subsequently integrated proteomic and transcriptomic data with H3K18la-specific chromatin immunoprecipitation (ChIP) sequencing to identify candidate genes involved in sublethal heat treatment-induced HCC cell metastasis. Mechanically, the upregulation of H3K18la modification enhances the transcriptional activity of NFS1, a key player in iron-sulfur clusters biosynthesis, thereby reducing the susceptibility of HCC to ferroptosis post IMWA. Knocking down NFS1 diminished the metastatic potential of sublethal heat-treated HCC cell. Additionally, the deficiency of NFS1 exhibited a synergistic effect with oxaliplatin, leading to a significant inhibition of the metastatic capability of HCC cells both in vitro and in vivo, regardless of HS treatment. In conclusion, our study reveals the oncogenic role of Histone lactylation in HCC after IMVA, we also bridge histone lactylation with ferroptosis, which provides novel therapeutic targets for HCC following microwave ablation, particularly when combined with oxaliplatin-based chemotherapy.
2025-03-12 | GSE279569 | GEO
Project description:Lysine lactylation is a lactate-induced post-translational modification that links cellular metabolism to biological processes. However, the functional role of this histone mark in cancers remains largely unexplored, partly due to a lack of knowledge about its reader proteins. Here, we identify SMARCA5 as a bona fide effector of H3K18la. Transcriptomics, metabolomics and epigenetics analyses reveal numerous SMARCA5 target genes, enriched for metabolic regulators including HK2, PFKM, and LDHA. We further demonstrate that SMARCA5 facilitates glycolytic activity by recruiting MYC to the promoters of glycolytic genes. Elevated lactate derived from tumor glycolysis similarly increases H3K18la levels in CD8+ T cells and induces inhibitory receptor expression. Consequently, the glycolysis/H3K18la/SMARCA5/MYC positive feedback loop exacerbates tumor metabolism and promotes immune evasion. Pharmacologic inhibitor of LDHA that interrupts this loop attenuates immune evasion and sensitizes cancer cells to immunotherapy. Collectively, we propose SMARCA5 as a bona fide H3K18la reader that promotes tumor progression and immune escape by coupling cellular metabolism to epigenetic regulation.
2025-09-15 | GSE307050 | GEO
Project description:Lysine lactylation is a lactate-induced post-translational modification that links cellular metabolism to biological processes. However, the functional role of this histone mark in cancers remains largely unexplored, partly due to a lack of knowledge about its reader proteins. Here, we identify SMARCA5 as a bona fide effector of H3K18la. Transcriptomics, metabolomics and epigenetics analyses reveal numerous SMARCA5 target genes, enriched for metabolic regulators including HK2, PFKM, and LDHA. We further demonstrate that SMARCA5 facilitates glycolytic activity by recruiting MYC to the promoters of glycolytic genes. Elevated lactate derived from tumor glycolysis similarly increases H3K18la levels in CD8+ T cells and induces inhibitory receptor expression. Consequently, the glycolysis/H3K18la/SMARCA5/MYC positive feedback loop exacerbates tumor metabolism and promotes immune evasion. Pharmacologic inhibitor of LDHA that interrupts this loop attenuates immune evasion and sensitizes cancer cells to immunotherapy. Collectively, we propose SMARCA5 as a bona fide H3K18la reader that promotes tumor progression and immune escape by coupling cellular metabolism to epigenetic regulation.
2025-09-15 | GSE307047 | GEO