ArticleCancer research2025
A Citrate Synthase Splice Variant Rewires the TCA Cycle to Promote Colorectal Cancer Progression.
Article in Cancer research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
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- Article
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- The pyruvate branch point controls lymphoid cancer cell dissemination.bioRxiv : the preprint server for biology · 2026Article
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Abstract
Metabolic reprogramming, notably alterations in the tricarboxylic acid (TCA) cycle, has emerged as a hallmark of cancer that supports tumor growth and metastasis. Despite the TCA cycle being a classical central metabolic pathway, further exploration is needed to fully elucidate the intricate manifestations and contributory mechanisms of TCA cycle rewiring in colorectal carcinogenesis. In this study, we identified a splicing isoform of citrate synthase (CS), CS-ΔEx4, and unveiled its role in TCA cycle dysregulation in colorectal cancer. CS-ΔEx4 was distinctly upregulated in colorectal cancer tumors compared with the canonical CS full-length (CS-FL) isoform. Clinical analyses established a strong correlation between elevated CS-ΔEx4 expression and cancer recurrence as well as inferior survival outcomes in patients with colorectal cancer. Functional experiments revealed the active contribution of CS-ΔEx4 to the aggressive phenotype of colorectal cancer cells both in vitro and in vivo. Mechanistically, CS-ΔEx4 formed a heterocomplex with CS-FL within the mitochondria that influenced the enzymatic function of canonical CS and accelerated TCA cycle flux, thereby promoting the accumulation of the oncometabolite 2-hydroxyglutarate. The CS-ΔEx4-mediated metabolic alterations engendered epigenomic modulations that drove the upregulation of oncogenic gene signatures. In silico screening identified a small molecule with potent antiproliferative effects in colorectal cancer cell line and organoid models that selectively antagonized the CS-ΔEx4 and CS-FL heterocomplex activity while sparing the CS-FL homodimers. Together, this study discovered the presence of a spliced CS isoform that promotes colorectal cancer progression and identified a molecule that holds potential for targeting the CS-ΔEx4 and CS-FL heterocomplex. SIGNIFICANCE: The citrate synthase variant CS-ΔEx4 augments TCA metabolic flux to facilitate epigenetic reprogramming and colorectal carcinogenesis and can be targeted with a small molecule, providing a promising treatment strategy for colorectal cancer. See related commentary by Schatton and Frezza, p. 4293.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.