Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1288022 | ENA |
REPOSITORIES: ENA
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Project description:Cancer immunotherapy has reshaped the landscape of cancer treatment, but its effectiveness is limited by tumor immunosuppression caused by excessive lactate production by cancer cells. While efforts to reduce lactate levels through lactate dehydrogenase inhibition have been made, such inhibitors can disrupt the metabolism of healthy cells and cause severe non-specific toxicity. Based on lactate oxidase, we report herein an enzyme therapeutic, which reduces lactate levels, releases an immunostimulatory molecule-hydrogen peroxide, averts tumor immunosuppression, and synergistically improves the efficacy of immune checkpoint blockades, as demonstrated in a murine melanoma model and a humanized mouse model of triple-negative breast cancer.
2024-05-10 | GSE230896 | GEO
Project description:Calcific aortic valvular disease (CAVD) is characterized by progressive thickening and calcification of the valvular leaflets. Emerging evidence suggests that glycolysis, particularly regulated by pyruvate dehydrogenase kinase 4 (PDK4), plays a significant role in calcification-related diseases. Nevertheless, the mechanisms by which PDK4 affects glycolysis and influences CAVD remain unexplored. This study investigated the contribution of PDK4 to glycolytic reprogramming and osteogenic differentiation in CAVD. Osteogenic differentiation of human valvular interstitial cells (VICs) and CAVD valves was associated with enhanced glycolysis, leading to increased lactate production that further promoted VICs' calcification. PDK4 expression was significantly upregulated in both osteogenically differentiated VICs and CAVD valves. Silencing PDK4 reduced osteogenic differentiation in VICs, whereas PDK4 overexpression aggravated differentiation and increased glycolytic activity. Mechanistically, PDK4 facilitated nuclear translocation of Yes-associated protein (YAP), a key regulator of the Hippo signaling pathway, thereby enhancing RUNX2 transcription and promoting osteogenic differentiation. Nuclear accumulation of lactate increased H3K18 lactylation, which stabilized PDK4 mRNA through the METTL3-m6A-YTHDF1 pathway, establishing a positive feedback loop. This study identifies mechanisms by which glycolysis drives CAVD progression and highlights PDK4 as a potential molecular target for therapeutic intervention.
2026-05-01 | GSE309849 | GEO
Project description:Calcific aortic valvular disease (CAVD) is characterized by progressive thickening and calcification of the valvular leaflets. Emerging evidence suggests that glycolysis, particularly regulated by pyruvate dehydrogenase kinase 4 (PDK4), plays a significant role in calcification-related diseases. Nevertheless, the mechanisms by which PDK4 affects glycolysis and influences CAVD remain unexplored. This study investigated the contribution of PDK4 to glycolytic reprogramming and osteogenic differentiation in CAVD. Osteogenic differentiation of human valvular interstitial cells (VICs) and CAVD valves was associated with enhanced glycolysis, leading to increased lactate production that further promoted VICs' calcification. PDK4 expression was significantly upregulated in both osteogenically differentiated VICs and CAVD valves. Silencing PDK4 reduced osteogenic differentiation in VICs, whereas PDK4 overexpression aggravated differentiation and increased glycolytic activity. Mechanistically, PDK4 facilitated nuclear translocation of Yes-associated protein (YAP), a key regulator of the Hippo signaling pathway, thereby enhancing RUNX2 transcription and promoting osteogenic differentiation. Nuclear accumulation of lactate increased H3K18 lactylation, which stabilized PDK4 mRNA through the METTL3-m6A-YTHDF1 pathway, establishing a positive feedback loop. This study identifies mechanisms by which glycolysis drives CAVD progression and highlights PDK4 as a potential molecular target for therapeutic intervention.
2026-05-01 | GSE309520 | GEO
Project description:We analyzed RNA levels in Drosophila Lactate Dehydrogenase mutants and precise excision controls during mid-L2 development.
2019-09-01 | GSE119334 | GEO
Project description:Histone acetylation involves the transfer of a two-carbon unit to nucleus as embedded in low-concentration metabolites. We find that lactate, a high-concentration metabolic by-product, can be a major carbon source for histone acetylation, through oxidation-dependent metabolism. Both in cells and in purified nucleus, 13C3-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), the knockout of which abrogates the incorporation. Heterologous expression of nucleus-localized LDHA rescues the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces the acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence of the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing the disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism-epigenetics axis controlled by cell’s own or environmental status.
2023-11-21 | GSE235471 | GEO
Project description:We found that lactate and lactylation were significantly elevated in rotator cuff tears, and lactylation primarily regulates histones in tenocytes. Therefore, we screened for histone lactylation and identified that H3K9, H4K8, and H4K16 had the most prominent increases. Subsequently, we conducted CUT - Tag assays on them. The results indicated that H3K9la was enriched at the promoters of ENO3 and COL1, while H4K16la was enriched at the promoter of TNMD, which induced the transcriptional expression of these genes. Moreover, as a glycolytic enzyme, ENO3 is further involved in the H3K9la–Eno3–lactate–H3K9la positive feedback loop to maintain a high lactate level. This feedback loop continuously drives the H3K9 - COL1 and H4K16 - TNMD regulatory axes, ultimately promoting the repair of rotator cuff tear injuries.
2025-09-30 | GSE309143 | GEO
Project description:Lactate is abundant in the tumor environment as the secreted product of fermentative cells. In prostate cancer (PCa), cancer-associated fibroblasts are the major contributors and this secreted lactate is uptaken by cancer cells to sustain their mitochondrial metabolism. However, how lactate controls the metabolic and transcriptional regulation in tumors is far to be elucidated. Here, we identify an innovative lactate-driven mechanism able to increase the expression of genes involved in lipid metabolism in PCa cells. This regulation enhances intracellular lipid accumulation in lipid droplets (LDs) and provides acetyl moieties for histone acetylation, establishing a regulatory loop between metabolites and epigenetic control. Interestingly, inhibition of this loop by targeting bromodomains histone acetylation readers suppresses the expression of perilipin-2 (PLIN2), a crucial component of LDs, disrupting the lactate-dependent lipid metabolic rewiring. Since this metabolic-epigenetic regulatory loop sustains PCa metastatic potential, its targeting is of clinical relevance as demonstrated by the inhibition of PCa invasive potential in vivo. Overall, our findings show that lactate has both a metabolic and an epigenetic role in promoting PCa progression.
2022-01-31 | GSE195639 | GEO
Project description:Corynebacterium glutamicum is able to grow with lactate as sole or combined carbon and energy source. Quinone-dependent L-lactate dehydrogenase LldD is known to be essential for utilization of L-lactate by C. glutamicum. D-lactate also serves as sole carbon source for C. glutamicum ATCC 13032. Here, the gene cg1027 was shown to encode the quinone-dependent D-lactate dehydrogenase (Dld) by enzymatic analysis of the protein purified from recombinant E. coli. The absorption spectrum of purified Dld indicated the presence of FAD as bound cofactor. Inactivation of dld resulted in the loss of the ability to grow with D-lactate, which could be restored by plasmid-borne expression of dld. Heterologous expression of dld from C. glutamicum ATCC 13032 in C. efficiens enabled this species to grow with D-lactate as sole carbon source. Homologs of dld of C. glutamicum ATCC 13032 are not encoded in the sequenced genomes of other corynebacteria and mycobacteria. However, the dld locus of C. glutamicum ATCC 13032 shares 2367 bp of 2372 bp identical nucleotides with the dld locus of Propionibacterium freudenreichii subsp. shermanii, a bacterium used in Swiss-type cheese making. Both loci are flanked by insertion sequences of the same family suggesting a possible event of horizontal gene transfer.
2010-12-02 | GSE25704 | GEO
Project description:Eubacterium limosum is a dominant member of the human gut microbiome and produces short-chain fatty acids (SCFAs). These promote immune system function and inhibit inflammation, making this microbe important for human health. Lactate is a primary source of gut SCFAs but its utilization by E. limosum has not been explored. We show that E. limosum growing on lactate takes up added tungstate rather than molybdate and produces the SCFAs acetate and butyrate, but not propionate. The genes encoding an electron bifurcating, tungsten-containing oxidoreductase (WOR1) and a tungsten-containing formate dehydrogenase (FDH), along with an electron bifurcating lactate dehydrogenase (LCT), lactate permease and enzymes of the propanediol pathway, are all up-regulated on lactate compared to growth on glucose. Lactate metabolism is controlled by a GntR-family repressor (LctR) and two global regulators, Rex and CcpA, where Rex in part controls W storage and tungstopyranopterin (Tuco) biosynthesis. Tuco-dependent riboswitches, along with CcpA, also control two iron transporters, consistent with the increased iron demand for many iron-containing enzymes, including WOR1 and FDH, involved in SCFA production. From intracellular aldehyde concentrations and the substrate specificity of WOR1, we propose that WOR1 is involved in detoxifying acetaldehyde produced during lactate degradation. Lactate to SCFA conversion by E. limosum is clearly highly tungstocentric and tungsten might be an overlooked micronutrient in the human microbiome and in overall human health.
2025-11-06 | GSE281261 | GEO
Project description:Protein lactylation is a process that is fueled by lactate, generated by the enzyme lactate dehydrogenase (Ldh) from pyruvate. Despite prior research, the precise role of protein lactylation in controlling the identity of mouse embryonic stem cells (ESCs) is still not fully understood. We observed that inhibiting or eliminating Ldha causes a reduction in global protein lactylation in ESCs, and RNA-seq analysis suggests that Ldha inhibition induces a 2-cell-like cell (2CLC) signature in ESCs. To probe the underlying mechanisms, we performed quantitative lactylation proteomics analysis, we discovered that Hdac1, a gene with significant regulatory roles during the 2-cell stage (2C), undergoes lactylation modification. Additionally, we observed that treatment with an Ldh (lactate dehydrogenase) inhibitor can decrease the lactylation levels of Hdac1. Mechanistically, we discovered that Ldha positively regulates the lactylation of Hdac1, promoting its direct binding to zygotic genome activation (ZGA) gene promoters and has stronger deacetylase activity. This leads to the removal of acetyl groups from H3K27 on these loci, effectively suppressing the expression of 2C genes. Our study presents novel evidence supporting protein lactylation's potential as a means of inhibiting the generation of 2CLCs and modulating acetylation activity.
2024-11-07 | GSE247958 | GEO