Esophageal squamous cell carcinoma remains one of the most lethal malignancies in the world, and a study published on 9 July 2026 in the journal Cancer & Metabolism now adds a metabolic dimension to the search for its vulnerabilities. The research, led by Weiling Liu, Yangyang Hou, Shujun Yang and Yan Zhao together with colleagues, reports that the signaling protein VAV2 acts as an oncoprotein driving glycolytic reprogramming in esophageal squamous cell carcinoma, a process in which tumor cells preferentially ferment glucose rather than relying on mitochondrial respiration. The work, published open access as Volume 14, article number 25, traces this metabolic shift through a previously unrecognized regulatory chain: VAV2 upregulates a protein called EIF3F, which in turn removes ubiquitin tags from MTA1, stabilizing it. Stabilized MTA1 then activates HIF-1α, a transcription factor that switches on the glucose transporter GLUT1 and the lactate-producing enzyme LDHA, together rewiring how the cancer cell generates energy.
The significance of this axis lies in the way it connects three layers of tumor biology that are usually studied separately: signal transduction, protein degradation and metabolism. VAV2 is a guanine nucleotide exchange factor, a class of proteins best known for activating Rho-family GTPases that control the cytoskeleton, migration and proliferation. Its overexpression has been reported in breast cancer, prostate cancer and head and neck squamous cell carcinoma, and the same team had previously shown that VAV2 supports DNA repair and radioresistance in esophageal cancer cells. The new study extends this picture by asking whether VAV2 also shapes the metabolic phenotype of the tumor. The answer, according to the authors, is yes, and the mechanism runs through protein stability rather than through changes in gene transcription of the metabolic enzymes themselves.
The first step was to establish that VAV2 is indeed elevated in the disease. Using single-cell RNA sequencing data from the public GSE203067 cohort, the researchers found that VAV2 expression was markedly higher in tumor epithelial cells than in normal epithelial cells of esophageal squamous cell carcinoma tissues. Bulk transcriptome data pointed the same way: in the TCGA esophageal carcinoma cohort, primary tumors showed higher VAV2 levels than normal tissues, with one analysis comparing 182 tumors against 286 peritumoral normal samples and a second comparing 184 primary tumors against 11 normal samples. A receiver operating characteristic analysis yielded an area under the curve of 0.791 for distinguishing tumor from normal tissue, which the authors describe as moderate diagnostic accuracy. VAV2 levels were also significantly higher in Stage II–IV tumors than in Stage I tumors, suggesting an association with more advanced disease.
With overexpression established, the team moved to functional tests in cell lines. Transcriptome sequencing of VAV2-knockdown KYSE150 cells showed that differentially expressed genes were enriched in metabolic processes, and single-sample gene set enrichment analysis revealed that VAV2 knockdown reduced the enrichment score of the glycolytic process gene set. The researchers then generated VAV2-overexpressing and VAV2-knockout KYSE150 cells, confirmed by Western blot. VAV2 overexpression increased glucose uptake by roughly 2.1-fold and lactate production by roughly 2.3-fold, while VAV2 knockout reduced glucose uptake by about 45 percent and lactate production by about 55 percent. Seahorse extracellular flux analysis added a biophysical layer: overexpression raised the extracellular acidification rate, a readout of glycolytic activity, and lowered the oxygen consumption rate, whereas knockout produced the opposite pattern. Parallel experiments in KYSE450 cells reproduced these findings, indicating that the effect is not confined to a single cell line.
To find the mediator, the investigators crossed proteomic and transcriptomic datasets. DIA proteomics data from VAV2-knockout cells, reanalyzed from the team’s earlier work, pointed to MTA1, a core component of the NuRD chromatin-remodeling complex, as a candidate downstream effector. Enrichment analysis showed that VAV2 knockdown correlated with suppression of HIF-1α pathway gene sets. Notably, VAV2 overexpression changed MTA1 protein levels without altering MTA1 mRNA, a signature of post-translational regulation. Western blotting confirmed that VAV2 overexpression increased MTA1 protein while knockdown decreased it, and that VAV2 overexpression upregulated HIF-1α and its target LDHA, whereas knockdown reduced HIF-1α, GLUT1 and LDHA. Rescue experiments showed that silencing MTA1 partially reversed the VAV2-driven increase in HIF-1α, GLUT1 and LDHA, and pulled glucose uptake back to roughly 0.49-fold and lactate production to roughly 0.46-fold of the levels seen with VAV2 overexpression alone.
The biochemistry of MTA1 stabilization came into focus through a series of classical protein-degradation assays. Cycloheximide chase experiments, which block new protein synthesis and track the decay of existing protein, showed that VAV2 overexpression prolonged the half-life of MTA1 in both KYSE150 and KYSE450 cells. Treatment with MG132, a proteasome inhibitor, abolished the drop in MTA1 protein caused by VAV2 knockdown, implicating the ubiquitin-proteasome pathway. Ubiquitination assays then demonstrated that VAV2 overexpression significantly reduced the ubiquitination of MTA1. In a related set of experiments, the team showed that MTA1 binds HIF-1α, prolongs its half-life, and reduces its ubiquitination, thereby protecting the transcription factor from proteasomal degradation under normoxic conditions. Together these results place MTA1 as a stabilizing partner of HIF-1α and VAV2 as the upstream guardian of MTA1 itself.
The missing link was the enzyme that actually removes the ubiquitin. By integrating DIA proteomics, immunoprecipitation-mass spectrometry and ubiquitination datasets, the researchers identified EIF3F, a subunit of the eukaryotic translation initiation factor 3 complex that carries an intrinsic JAMM/MPN-domain deubiquitinase activity. Molecular docking predicted binding interfaces between VAV2 and EIF3F and between EIF3F and MTA1, and co-immunoprecipitation confirmed that endogenous VAV2 interacts with endogenous EIF3F, and that EIF3F binds MTA1, in KYSE150 cells, with immunofluorescence showing cytoplasmic colocalization. VAV2 overexpression increased EIF3F protein levels and knockout decreased them, and RT-qPCR plus dual-luciferase reporter assays indicated that VAV2 upregulates EIF3F primarily at the transcriptional level. Functionally, EIF3F overexpression reduced MTA1 ubiquitination in 293T cells, preferentially cleaving K48-linked polyubiquitin chains, the canonical degradation signal, while leaving K63-linked chains untouched. A deubiquitinase-dead mutant, EIF3F-ΔMPN, failed to rescue MTA1 stability in VAV2-knockdown cells, confirming that the catalytic activity, rather than the translation function of EIF3F, is what matters here.
The axis was then tested in living animals. The team implanted KYSE150 cells into female BALB/c nude mice, with six animals per group and four experimental conditions combining VAV2 overexpression or vector control with EIF3F knockdown or a non-targeting control. Tumors derived from VAV2-overexpressing cells grew faster, reaching roughly 1.6-fold greater volume by day 28, with larger final volumes and weights than controls. Knocking down EIF3F partially reversed this, reducing tumor volume and weight by approximately 43 percent. Western blotting of excised tumors confirmed that EIF3F knockdown blunted the VAV2-driven upregulation of MTA1, HIF-1α, GLUT1 and LDHA, and immunohistochemistry showed reduced staining for these proteins and for the proliferation marker Ki67. In vitro rescue experiments completed the loop: overexpressing EIF3F in VAV2-deficient cells restored downstream marker expression and reversed the glycolytic defects to near-control levels, positioning EIF3F as the functional dependency through which VAV2 acts.
The authors are candid about the boundaries of the work. The precise mechanism by which VAV2 upregulates EIF3F, whether through transcriptional activation, mRNA stabilization or translational enhancement, remains to be fully resolved, although bioinformatic analysis identified potential c-Myc binding motifs in the EIF3F promoter and the VAV2-Rac1 axis is known to activate c-Myc. The team did not perform in vitro reconstitution assays with purified proteins, and because EIF3F is a JAMM-domain deubiquitinase that may require cofactors or the intact eIF3 complex for full activity, structural and biochemical studies will be needed to define the catalytic mechanism. Whether the axis operates in cancers beyond esophageal squamous cell carcinoma is unknown, its clinical value as a prognostic biomarker or therapeutic target has not been tested in large patient cohorts, and the subcutaneous xenograft model does not recapitulate the organ-specific tumor microenvironment, so orthotopic and patient-derived models will be essential next steps. Within those limits, the study maps a signaling-to-deubiquitination-to-metabolism circuit and proposes that disrupting the VAV2-EIF3F interaction could one day undermine the glycolytic dependence that helps these tumors resist therapy.
Subject of Research: VAV2-driven glycolytic reprogramming in esophageal squamous cell carcinoma via the EIF3F-MTA1-HIF-1α axis
Article Title: VAV2 drives glycolytic reprogramming in esophageal squamous cell carcinoma via EIF3F-mediated MTA1 deubiquitination
Article References: Liu, W., Hou, Y., Wang, B., Liu, F., Zheng, L., Wang, H., Li, S., Zhou, X., Zhang, M., Yang, S., & Zhao, Y. (2026). VAV2 drives glycolytic reprogramming in esophageal squamous cell carcinoma via EIF3F-mediated MTA1 deubiquitination. Cancer & Metabolism, 14(1), Article 25. https://doi.org/10.1186/s40170-026-00447-0
Image Credits: AI Generated
DOI: 10.1186/s40170-026-00447-0
Keywords: esophageal squamous cell carcinoma, VAV2, EIF3F, MTA1, HIF-1α, aerobic glycolysis, Warburg effect, deubiquitination, xenograft model, metabolic reprogramming, cancer metabolism, drives
News Source: Nathaniel Bowman. (October 30, 2026). Study reveals how VAV2 fuels glycolysis in esophageal squamous cell carcinoma. Scienmag.
