Lactate Marks on Histones Drive Wilms Tumor Growth Through a Self-Reinforcing Genetic Loop

Scientists have uncovered a previously unknown molecular engine that drives the malignant progression of Wilms tumor, the most common kidney cancer in children. The discovery centers on a chemical modification called histone lactylation, in which lactate—the end product of sugar metabolism—is attached to histone proteins that package DNA. When this modification accumulates on a specific histone site known as H3 lysine 18, it switches on a gene called PSRC1, which in turn ignites a powerful cancer-promoting signaling cascade and ultimately feeds back to amplify its own production. The finding, published in Advanced Science, reveals a self-reinforcing circuit that could offer new targets for treating the most dangerous forms of this childhood cancer.

Wilms tumor, also known as nephroblastoma, arises in the developing kidney and accounts for the vast majority of pediatric renal malignancies. More than 90 percent of children are diagnosed with the favorable-histology form, but outcomes vary considerably across patient cohorts. The picture is far grimmer for the 5 to 10 percent of cases classified as high-risk—including metastatic blastemal-type tumors, diffuse anaplastic disease, chemotherapy-refractory tumors, and multiply relapsed cancers—which carry survival rates below 50 percent even after aggressive multimodal therapy. Survivors of intensive radiochemotherapy frequently endure severe long-term side effects that diminish their quality of life. These realities have long motivated researchers to search for molecular vulnerabilities that could enable more individualized and less toxic treatments.

The new study began with a well-known hallmark of cancer: metabolic reprogramming. Tumor cells preferentially break down glucose into lactate even when oxygen is abundant, a phenomenon called the Warburg effect, leading to lactate buildup in the tumor microenvironment. Previous metabolomics work had already flagged elevated lactate as a signature distinguishing Wilms tumor tissue from normal kidney tissue, and a retrospective cohort study showed that higher lactate dehydrogenase activity independently predicts increased recurrence risk in pediatric patients. The research team confirmed these patterns directly, analyzing 52 pairs of Wilms tumor specimens and matched adjacent normal tissues collected at Qilu Hospital of Shandong University. Tumor tissues contained significantly less glucose and significantly more lactate than their normal counterparts, consistent with hyperactive glycolysis.

Lactate, once dismissed as a mere metabolic waste product, is now understood to be a versatile molecule that serves as an energy substrate, a signaling agent, and—critically—an epigenetic regulator. In 2019, researchers first identified histone lactylation as a novel epigenetic modification that directly modulates gene transcription on chromatin. Since then, histone lactylation has been implicated in immune evasion, metabolic reprogramming, and therapeutic resistance across many cancers. The process is enzyme-dependent: the acetyltransferase p300 acts as a writer that deposits lactyl groups onto histones, while HDAC1-3 and sirtuins serve as erasers that remove them. Because these same enzymes also manage histone acetylation, the two modifications share overlapping machinery, raising the possibility that lactylation plays an important but overlooked role in Wilms tumor biology.

Using immunohistochemistry and western blotting on the clinical specimens, the team found that pan-lysine lactylation and H3K18 lactylation were the most prominently elevated modifications in tumor tissue. Survival analysis showed that only high levels of these two marks correlated with significantly poorer event-free survival among the 52 patients studied. To probe function, the researchers manipulated lactylation levels in two Wilms tumor cell lines, WiT49 and WT-CLS1, using sodium lactate to raise intracellular lactate and the glycolysis inhibitors 2-deoxy-D-glucose and oxamate to lower it. The results were striking: boosting lactylation enhanced cell proliferation and migration in a dose-dependent manner, while suppressing lactylation markedly reduced these malignant behaviors.

To identify the genes controlled by H3K18 lactylation, the team integrated public ChIP-seq datasets with RNA-sequencing data from 126 Wilms tumor patients in the TARGET database. Cross-referencing genes bound by the H3K18la mark with genes upregulated in tumors yielded 302 candidates, which were then filtered through Cox regression analyses of patient survival data. Three genes emerged with independent prognostic significance: PSRC1, RFXAP, and GLRX3. Only PSRC1, however, responded specifically to changes in lactylation levels—its mRNA rose with sodium lactate treatment and fell with oxamate. Chromatin immunoprecipitation experiments confirmed that H3K18la was robustly enriched at the PSRC1 promoter in Wilms tumor cells, and that the writer enzyme p300 was required for this deposition. Importantly, the closely related acetylation mark H3K18ac remained unchanged across all treatments, demonstrating that p300 regulates PSRC1 specifically through lactylation rather than acetylation.

PSRC1 itself proved to be a potent oncogenic driver. The protein, also known as DDA3, is a mitotic regulator previously implicated in small cell lung cancer, breast cancer, and hepatocellular carcinoma. In Wilms tumor, high PSRC1 expression predicted poorer overall survival, with area under the curve values of 0.71 to 0.73 for one-, three-, and five-year survival predictions, and multivariate analysis confirmed it as an independent prognostic risk factor. Mechanistically, the team discovered that PSRC1 acts as a molecular competitor: it binds directly to the kinase domain of AKT through its proline-rich P-X-X-P domain spanning amino acids 103 to 246, thereby blocking the tumor suppressor PTEN from binding AKT and dephosphorylating it. Co-immunoprecipitation, mass spectrometry, immunofluorescence, and molecular docking—all supporting a stable interaction with a binding free energy of minus 28.4 kilocalories per mole—confirmed the competitive binding model. The consequence is sustained activation of the AKT/mTOR pathway, which stabilizes the HIF-1α protein, a master transcription factor that promotes glycolysis and tumor growth.

The final piece of the puzzle closed the loop. HIF-1α, stabilized by PSRC1-driven AKT signaling, was found to bind directly to a hypoxia response element within the PSRC1 promoter, further amplifying PSRC1 transcription. Dual-luciferase reporter assays demonstrated that hypoxia increased promoter activity only when the response element was intact, and HIF-1α knockdown blunted this activation. The result is a positive feedback circuit: H3K18 lactylation activates PSRC1, PSRC1 activates AKT/mTOR/HIF-1α signaling, and HIF-1α returns to boost PSRC1 expression, creating an escalating cycle of oncogenic signaling. Animal experiments corroborated the entire axis in vivo. In nude mouse xenograft models, PSRC1 knockdown slowed tumor growth and reduced lung metastatic burden, while PSRC1 overexpression accelerated growth, promoted lung colonization, and partially reversed the tumor-suppressive effects of oxamate, which was administered daily at 500 milligrams per kilogram.

The therapeutic implications are considerable, though tempered by practical challenges. The authors highlight three promising intervention points: inhibiting lactate production with agents such as oxamate, which has shown antitumor activity and low toxicity in preclinical models but suffers from poor membrane permeability that nanoparticle delivery could overcome; targeting the writer enzyme p300 with inhibitors such as CCS1477, which has advanced to phase I/II clinical trials in other cancers; and disrupting the feedback loop itself through AKT/mTOR inhibitors, peptide inhibitors designed to block the PSRC1-AKT interaction interface, or HIF-1α inhibitors. Each strategy faces hurdles, including systemic toxicity, the heightened safety requirements of pediatric oncology, and the risk that single-target inhibition will be undermined by the very feedback loop the study describes. The authors also note limitations: the clinical cohort was relatively small, genetically engineered animal models were not used, and the identity of the eraser enzymes that remove H3K18 lactylation in Wilms tumor remains unknown.

Nevertheless, the study represents the first demonstration of a histone lactylation-driven feedback circuit in Wilms tumor and bridges three previously separate domains—metabolic reprogramming, epigenetic modification, and oncogenic signaling. By showing that a metabolic byproduct can be converted into a durable transcriptional program that fuels cancer progression, the work adds Wilms tumor to the growing list of malignancies shaped by lactylation and provides a molecular rationale for combining metabolic inhibitors with signaling blockade. For the children with high-risk disease who currently face the bleakest odds, such rational combination strategies may ultimately offer a path toward more effective and less toxic therapy.

Subject of Research: Histone H3K18 lactylation and the PSRC1/AKT/HIF-1α feedback loop in Wilms tumor progression

Article Title: Histone H3K18 Lactylation Promotes the Malignant Progression of Wilms Tumor via a PSRC1/AKT/HIF‐1α Positive Feedback Loop

Article References: Wang, Y., Gao, H., Zhang, B., Li, X., Li, D., Cao, A., & Sun, F. (2026). Histone H3K18 Lactylation Promotes the Malignant Progression of Wilms Tumor via a PSRC1/AKT/HIF‐1α Positive Feedback Loop. Advanced Science, 13(56), Article e76579. https://doi.org/10.1002/advs.76579

Image Credits: AI Generated

DOI: 10.1002/advs.76579

Keywords: Wilms tumor, histone lactylation, H3K18la, PSRC1, AKT signaling, HIF-1α, p300, PTEN, Warburg effect, epigenetics, pediatric cancer, metabolic reprogramming