Jul 2026· Advancement of science· 0 citations· 52 references
Medicine
TL;DR
It is found that the hyperlactate microenvironment induced by abnormal glycolysis in WT significantly upregulates the level of histone H3K18 lactylation (H3K18la), which promotes WT cell proliferation and migration.
Abstract
ABSTRACT Nephroblastoma, also known as Wilms tumor (WT), is the most common pediatric renal malignancy. Current treatment regimens exhibit limited efficacy in high‐risk patients and are associated with long‐term adverse effects. Through gene set enrichment analysis (GSEA) and validation using clinical specimens, we identified aberrant glycolytic activity in WT, which drives lactate accumulation. Lactate is not merely a metabolic byproduct but also a critical epigenetic regulator that mediates histone lactylation; however, its functional role in WT remains uncharacterized. In this study, we found that the hyperlactate microenvironment induced by abnormal glycolysis in WT significantly upregulates the level of histone H3K18 lactylation (H3K18la). Functional experiments confirmed that histone lactylation promotes WT cell proliferation and migration. Mechanistically, H3K18la, catalyzed by its “writer” p300, directly marks the promoter region of the downstream target gene PSRC1 and transcriptionally activates its expression. PSRC1 then acts as a key “molecular competitor,” binding to AKT in a competitive manner with the phosphatase PTEN. This interaction relieves PTEN‐mediated dephosphorylation inhibition of AKT, thereby activating the AKT/mTOR signaling pathway and enhancing the protein stability of its downstream effector HIF‐1α. Concurrently, HIF‐1α functions as a transcription factor to directly bind to the PSRC1 promoter, synergizing with H3K18la to further amplify PSRC1 transcription. In summary, this study identifies a positive feedback loop: “H3K18la→PSRC1→AKT/mTOR→HIF‐1α→PSRC1.” This mechanism dynamically links tumor metabolic abnormalities, histone modifications, and key oncogenic signaling pathways, which collectively drive the malignant progression of WT. These findings provide a novel theoretical basis for the stratified diagnosis and targeted therapy of WT.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved outcomes in EGFR-mutant lung adenocarcinoma (LUAD), yet acquired resistance to the third-generation inhibitor osimertinib remains inevitable. Although metabolic reprogramming is increasingly recognized as a driver of therapeutic resistance, the epigenetic consequences of lactate accumulation and their functional relevance in osimertinib resistance are poorly understood. Here we report that osimertinib-resistant LUAD cells exhibit enhanced glycolytic flux, increased intracellular lactate levels, and elevated histone H4 lysine 8 lactylation (H4K8la). Integrative transcriptomic analysis revealed significant enrichment of cell-cycle–associated pathways in resistant tumors, despite downregulation of canonical Cyclin B1 and Cyclin D1. Among the upregulated genes, GAS2L3 emerged as a prominent candidate. Genome-wide CUT&Tag profiling demonstrated enrichment of H4K8la at the GAS2L3 promoter, which was confirmed by ChIP–qPCR. Functionally, GAS2L3 overexpression accelerated S/G2–M progression and promoted proliferation under drug pressure, whereas its silencing induced cell-cycle arrest and restored osimertinib sensitivity both in vitro and in xenograft models. Notably, resistant cells displayed elevated P53 expression without induction of its canonical effector P21, indicating checkpoint uncoupling and a noncanonical mode of cell-cycle regulation. Mechanistically, glycolysis inhibition reduced H4K8la and GAS2L3 expression and partially re-sensitized resistant cells, while exogenous lactate restored H4K8la levels and resistance phenotypes, establishing a metabolically driven epigenetic circuit. Clinically, high GAS2L3 expression was associated with shorter progression-free survival in osimertinib-treated patients. Collectively, our findings identify a glycolysis–H4K8la–GAS2L3 axis that drives noncanonical cell-cycle reprogramming independently of classical Cyclin–CDK activation, thereby promoting acquired osimertinib resistance. These results uncover a metabolism-epigenetics–cell cycle interface that may represent a therapeutic vulnerability in EGFR-mutant LUAD.
S. Zhen, Xiaohui Bai, Shutang Liu et al.· Cell Death Discovery· 0 citations
A novel metabolic-epigenetic mechanism whereby lactate modulates hepatocellular carcinoma sensitivity to targeted therapies through histone lactylation is delineated and suggests AARS1-H4K12la-RAPGEF3 axis may serve as an interventional target to overcome targeted drug resistance, offering a promising strategy to enhance clinical outcomes in HCC patients.
Tanlun Zeng, Wanwan Zhu, Guanqun Sun et al.· Cell Death and Disease· 1 citation
ABSTRACT Recurrence and progression remain major clinical challenges in bladder cancer (BC), yet the mechanisms linking glycolysis to persistent malignant states remain incompletely defined. Here, we identify alanyl tRNA synthetase 1 (AARS1) as a clinically relevant driver of aggressive and recurrent BC. AARS1 is upregulated in BC tissues, enriched in muscle invasive and recurrent tumors, and associated with unfavorable survival. Functionally, AARS1 promotes proliferation, epithelial mesenchymal transition, invasion, apoptosis resistance, tumor growth, and lung colonization. Mechanistically, AARS1 enhances phosphoinositide 3 kinase (PI3K) pathway output, glycolytic flux, and lactate production. Increased lactate availability is linked to histone H3 lysine 27 lactylation (H3K27la) enrichment at the hexokinase 2 (HK2) promoter, increased chromatin accessibility, and HK2 transcriptional activation, supporting an HK2 centered metabolic and epigenetic reinforcement program. HK2 perturbation attenuates AARS1 associated glycolytic and malignant phenotypes. Through structure guided screening and surface plasmon resonance validation, we further identified eltrombopag as an AARS1 binding compound that pharmacologically suppressed the AARS1 associated PI3K, glycolysis, lactate, H3K27la, and HK2 program and restrained tumor progression in preclinical models. These findings define an AARS1 associated metabolic and epigenetic program in BC and nominate AARS1 targeting strategies as a direction for further therapeutic development.
Qin Yuan, Tianbao Song, Yipeng He et al.· Advancement of science· 0 citations
ABSTRACT Tumor metabolic dysregulation is a critical determinant of tumor progression and response to immunotherapy. Aberrant glutamine metabolism is a hallmark of gastric cancer (GC). However, beyond fueling GC cell anabolism, its role in remodeling the immunosuppressive tumor microenvironment remains poorly understood. Here, we show that GC cells overexpress solute carrier family 1 member 5 (SLC1A5) to drive glutamine accumulation, which not only promotes their own proliferation but also reduces glutamine availability to CD8+ T cells, thereby suppressing antitumor immunity. These dual effects cooperatively drive GC progression. Mechanistically, loss of methyltransferase‐like protein 7A (METTL7A) stabilizes SLC1A5 mRNA by reducing its m6A modification. Concurrently, METTL7A deficiency increased N‐glycosyltransferase β‐1,4‐galactosyltransferase 5 (B4GALT5) expression. B4GALT5 stabilizes SLC1A5 via N‐glycosylation at the N212 site, which blocks K48‐linked polyubiquitination and proteasomal degradation. We identify the natural flavonoid luteolin as an agent that upregulates METTL7A expression, which subsequently downregulates SLC1A5 expression and inhibits GC progression. Furthermore, luteolin significantly enhances the efficacy of anti‐PD‐1 therapy in GC. Collectively, our findings reveal that SLC1A5‐mediated glutamine competition drives both tumor cell proliferation and immune evasion in GC, and suggest that targeting the METTL7A/SLC1A5 axis may represent a promising therapeutic strategy.
Mingjun Sun, Shuwei Dang, Dazhi Zhou et al.· Advancement of science· 0 citations
Prostate cancer (PCa) progression is strongly influenced by the metabolites available in the tumor microenvironment (TME), including lactic acid (LA), which is actively imported by PCa cells to boost mitochondrial metabolism and drive de novo collagen synthesis, sustaining increased malignancy. LA exploitation promotes the unbalance of tricarboxylic acid (TCA) cycle intermediates, particularly succinate and fumarate, well-known epigenetic modifiers for histone (de)methylation. Here, we show that the LA-induced increase in succinate levels affects the activating H3K4me3 methylation mark in PCa cells, promoting a pro-invasive phenotype. Notably, pharmacological targeting of H3K4me3 using OICR-9429 reduces LA-enhanced PCa cell invasiveness. Moreover, LA-induced H3K4me3 enrichment regulates the expression of procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 1 (PLOD1), a key enzyme involved in collagen maturation. Genetic impairment of PLOD1 reduces the LA-driven invasive potential of PCa cells, thereby highlighting PLOD1 as a crucial epigenetically regulated mediator of tumor invasion. Overall, our findings uncover a novel LA-fuelled metabolic-epigenetic axis that promotes the H3K4me3-mediated PLOD1 upregulation, consequently fostering PCa aggressiveness and unveiling a potential therapeutic vulnerability.
Marta Iozzo, Luigi Ippolito, E. Pranzini et al.· Cell Death and Disease· 0 citations
Colorectal cancer (CRC) is the third most common type of cancer worldwide and ranks among the leading causes of cancer-related deaths. During tumor progression, post-translational modifications, mainly the ubiquitin-proteasome system, are critical mediators of cellular metabolic reprogramming, including the metabolic changes of tumor development. Although TP53 mutations occur in approximately half of all CRC cases and could define their genetic makeup, precise therapeutic vulnerabilities remain largely unknown for the subgroup with wild-type p53. This study investigated the significant expression of Germ Cell-Specific Gene 2 (GSG2) in CRC. We demonstrated GSG2 is strongly increased in malignant colorectal tissues compared with adjacent benign tissues, and this high expression strongly predicts poor patient survival. Additionally, the results indicate that removing GSG2 effectively suppresses tumor growth in both in vitro systems and in vivo xenograft models. Mechanistically, GSG2 directly binds to the E3 ligase MDM2, and promoted MDM2-mediated ubiquitination and degradation of p53 in p53 wild-type CRC cells. Consequently, GSG2 enhances the cellular metabolic program, reprogramming glucose use toward aerobic glycolysis to meet the energy needs of uncontrolled growth. Thus, our findings reveal a novel way that p53 is silenced in cancers with wild-type TP53. GSG2 demonstrate control of the MDM2-p53 axis to promote the Warburg effect and drive CRC progression via p53 suppression.
Huaqiong Pan, Ji-peng Liu, Taifu Xiao et al.· American Journal of Cancer R...· 0 citations
