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Dysmetabolic-dependent α-ketoglutarate/succinate ratio imbalance impairs TDG function and base excision repair process increasing susceptibility to pancreatic cancer

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a high lethal cancer with poor prognosis and lack of effective therapeutic options. Chronic metabolic disorders, including obesity and type 2 diabetes, are established risk factors for PDAC and contribute to its unfavorable prognosis. Prolonged exposure to altered metabolic states induces aberrant fluctuations in specific metabolites, which can impact the epigenetic landscape and facilitate the acquisition of neoplastic lesions. Indeed, certain metabolites function as cofactors for epigenetic enzymes, modulating their activity. In this study, we explored the interplay between metabolism and epigenetics in PDAC tumorigenesis under dysmetabolic conditions, aiming to uncover novel vulnerabilities in pancreatic cancer. The link between dysmetabolism and PDAC was examined in LSL-KrasG12D; PDX-1-Cre mice (KC mice) exposed to high-fat diet (HFD). Untargeted metabolomic analysis of pancreatic tissue revealed altered free fatty acid levels and elevated S-adenosyl methionine (SAM) during tumor development in HFD-fed mice. Targeted metabolomics further showed increased succinate (SA) levels alongside reduced α-ketoglutarate (αKG) levels, indicating dysregulation of the DNA methylation pathway. Given these findings, the DNA demethylation complex of ten-to-eleven-translocation methylcytosine 1 (TET1) and thymine DNA glycosylase (TDG) was further investigated in human pancreatic ductal epithelial cells bearing KRAS mutation exposed to dysmetabolic mimicking culture conditions. We demonstrated that dysmetabolic stress disrupts quickly TET1/TDG function, leading to accumulation of iterative cytosine modifications, including 5-formylcytosine (5fC), and increased apurinic/apyrimidinic (AP) sites. Specifically, AP site accumulation was a consequence of TDG hyperactivation induced by direct binding of SA on its arginine residue 275. This TDG alteration, together with the methylation-prone metabolic environment, impairs the base excision repair (BER) pathway by hypermethylation of the promoters of DNA ligases 1 (LIG1) and 3 (LIG3) and thus inducing their downregulation. The resulting inhibition of single-strand break repair predisposes to genomic instability and promotes pancreatic preneoplastic lesion development. Our results reveal an unprecedented role of metabolic-epigenetic crosstalk in dysmetabolism-driven PDAC tumorigenesis. These findings highlight TDG as a novel therapeutic target and propose 5fC and AP sites as potential biomarkers for pancreatic cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE302730 | GEO | 2026/03/11

REPOSITORIES: GEO

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Project description:Background: Here, the role of α-ketoglutarate (αKG) in the epi-metabolic control of DNA demethylation has been investigated in therapeutically relevant cardiac mesenchymal cells (CMSCs) isolated from controls and type 2 diabetes donors. Methods & results: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing and gene specific GC methylation detection revealed an accumulation of 5mC, 5hmC and 5fC in the genomic DNA of human CMSCs isolated from diabetic (D) donors (D-CMSCs). Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high fat diet (HFD), injected with streptozotocin (STZ) or both in combination (STZ-HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of αKG synthesis in D-CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised thymine DNA glycosylase (TDG) and ten eleven translocation protein 1 (TET1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that αKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatched or 5fC. Accordingly, an exogenous source of αKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5fC accumulation thus partially mimicking the diabetic epigenetic landscape in cells of non- diabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of αKG-dehydrogenase, increased the αKG level in D- CMSCs and in the heart of HFD mice eliciting DNA demethylation, glucose uptake and insulin response. Conclusions: In this report we established that diabetes may epigenetically modify and compromise function of therapeutically relevant cardiac mesenchymal cells. Restoring the epi-metabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes.

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Dysmetabolic-dependent α-ketoglutarate/succinate ratio imbalance impairs TDG function and base excision repair process increasing susceptibility to pancreatic cancer

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