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Project description:Ferroptosis, a non-apoptotic programmed cell death marked by iron-dependent lipid peroxidation, is closely associated with cancer. Despite of intensive investigation about the molecular pathways underlying ferroptosis, the mechanism that determines the disparity of cancer cell vulnerability to ferroptosis remains unclear. Here we show that the expression level of TET1, the founding member of the ten-eleven translocation (TET) family of enzymes that mediate DNA 5-hydroxymethylation, determines the susceptibility of cancer cells to ferroptosis. In ferroptosis resistant cells, the expression level of TET1 was remarkably higher than that of the sensitive cells. Cell response to ferroptosis could be affected by interfering TET1 expression. TET1 promoted DNA 5hmC modification at its target gene GCLM, activated both the canonical glutathione (GSH) synthesis, and the non-cannonical γ-glutamyl-peptide accumulation, and thus, protected cancer cells against ferroptosis. Our results uncover the role of TET1 as a ferroptotic defensor in cancer, and suggest the translational potential of targeting the TET/GCLM axis in cancer therapy.
2025-12-05 | GSE240526 | GEO
Project description:Ferroptosis, a non-apoptotic programmed cell death marked by iron-dependent lipid peroxidation, is closely associated with cancer. Despite of intensive investigation about the molecular pathways underlying ferroptosis, the mechanism that determines the disparity of cancer cell vulnerability to ferroptosis remains unclear. Here we show that the expression level of TET1, the founding member of the ten-eleven translocation (TET) family of enzymes that mediate DNA 5-hydroxymethylation, determines the susceptibility of cancer cells to ferroptosis. In ferroptosis resistant cells, the expression level of TET1 was remarkably higher than that of the sensitive cells. Cell response to ferroptosis could be affected by interfering TET1 expression. TET1 promoted DNA 5hmC modification at its target gene GCLM, activated both the canonical glutathione (GSH) synthesis, and the non-cannonical γ-glutamyl-peptide accumulation, and thus, protected cancer cells against ferroptosis. Our results uncover the role of TET1 as a ferroptotic defensor in cancer, and suggest the translational potential of targeting the TET/GCLM axis in cancer therapy.
2025-12-05 | GSE240525 | GEO
Project description:Ferroptosis, a non-apoptotic programmed cell death marked by iron-dependent lipid peroxidation, is closely associated with cancer. Despite of intensive investigation about the molecular pathways underlying ferroptosis, the mechanism that determines the disparity of cancer cell vulnerability to ferroptosis remains unclear. Here we show that the expression level of TET1, the founding member of the ten-eleven translocation (TET) family of enzymes that mediate DNA 5-hydroxymethylation, determines the susceptibility of cancer cells to ferroptosis. In ferroptosis resistant cells, the expression level of TET1 was remarkably higher than that of the sensitive cells. Cell response to ferroptosis could be affected by interfering TET1 expression. TET1 promoted DNA 5hmC modification at its target gene GCLM, activated both the canonical glutathione (GSH) synthesis, and the non-cannonical γ-glutamyl-peptide accumulation, and thus, protected cancer cells against ferroptosis. Our results uncover the role of TET1 as a ferroptotic defensor in cancer, and suggest the translational potential of targeting the TET/GCLM axis in cancer therapy.
2025-12-05 | GSE240524 | GEO
Project description:TET1-mediated DNA hydroxymethylation controlling ferroptosis resistance in cancer
| PRJNA1004170 | ENA
Project description:TET1-mediated DNA hydroxymethylation controlling ferroptosis resistance in cancer [RNA-seq]
| PRJNA1004180 | ENA
Project description:TET1-mediated DNA hydroxymethylation controlling ferroptosis resistance in cancer [ChIP-seq]
| PRJNA1004182 | ENA
Project description:TET1-mediated DNA hydroxymethylation controlling ferroptosis resistance in cancer [5hmC-seq]
| PRJNA1004179 | ENA
Project description:The mechanisms regulating myelin repair in the adult central nervous system (CNS) are unclear. Here, we identify DNA hydroxymethylation, catalyzed by the Ten-Eleven-Translocation (TET) enzyme TET1, as necessary for myelin repair in young adults and defective in old mice. Constitutive and inducible oligodendrocyte lineage-specific ablation of Tet1 (but not of Tet2), recapitulate this age-related decline in repair of demyelinated lesions. DNA hydroxymethylation and transcriptomic analyses identify TET1-target in adult oligodendrocytes, as genes regulating neuro-glial communication, including the solute carrier (Slc) gene family. Among them, we show that the expression levels of the Na+/K+/Cl- transporter, SLC12A2, are higher in Tet1 overexpressing cells and lower in old or Tet1 knockout. Both aged mice and Tet1 mutants also present inefficient myelin repair and axo-myelinic swellings. Zebrafish mutants for slc12a2b also display swellings of CNS myelinated axons. Our findings suggest that TET1 is required for adult myelin repair and regulation of the axon-myelin interface.
| S-EPMC8185117 | biostudies-literature
Project description:Oxaliplatin is the main chemotherapy drug for gastric cancer (GC), but quite a few patients are resistant to oxaliplatin, which contributes to the poor prognosis of GC patients. There is therefore an urgent need to identify potential targets for reversing chemotherapy resistance in GC patients. In this study, we analyzed the tumor samples of GC patients who received neoadjuvant chemotherapy based on oxaliplatin through quantitative proteomics and identified the potential chemoresistance-related protein cellular retinoic acid binding protein 2 (CRABP2). CRABP2 was significantly upregulated in the tumor tissues of chemoresistant GC patients and was closely related to prognosis. The results of cell function experiments showed that CRABP2 can promote the oxaliplatin resistance of GC cells in vitro. Coimmunoprecipitation and GST pulldown assays showed that CRAPB2 expedited the binding of BAX and PARKIN in GC cells and facilitated the ubiquitination-mediated degradation of BAX. Furthermore, both the in vitro assay and cell-derived xenograft (CDX) in vivo model verified that CRABP2 promoted oxaliplatin resistance by inhibiting BAX-dependent cell apoptosis. Further experiments proved that the abnormally high expression of CRABP2 in oxaliplatin-resistant GC cells was affected by TET1-mediated DNA hydroxymethylation. The patient-derived xenograft (PDX) model suggested that interference with CRABP2 reversed oxaliplatin resistance in GC in vivo. In conclusion, the results of our study show that CRABP2 was a key molecule in oxaliplatin resistance regulation and could be a new target for reversing the chemoresistance of GC.
| S-EPMC9532395 | biostudies-literature
Project description:Methylated cytosines are associated with gene silencing. The ten-eleven translocation (TET) hydroxylases, which oxidize methylated cytosines to 5-hydroxymethylcytosine (5hmC), are essential for cytosine demethylation. Gene silencing and activation are critical for intestinal stem cell (ISC) maintenance and differentiation, but the potential role of TET hydroxylases in these processes has not yet been examined. Here, we generated genome-wide maps of the 5hmC mark in ISCs and their differentiated progeny. Genes with high levels of hydroxymethylation in ISCs are strongly associated with Wnt signaling and developmental processes. We found Tet1 to be the most abundantly expressed Tet gene in ISCs; therefore, we analyzed intestinal development in Tet1-deficient mice and determined that these mice are growth-retarded, exhibit partial postnatal lethality, and have significantly reduced numbers of proliferative cells in the intestinal epithelium. In addition, the Tet1-deficient intestine displays reduced organoid-forming capacity. In the Tet1-deficient crypt, decreased expression of Wnt target genes such as Axin2 and Lgr5 correlates with lower 5hmC levels at their promoters. These data demonstrate that Tet1-mediated DNA hydroxymethylation plays a critical role in the epigenetic regulation of the Wnt pathway in intestinal stem and progenitor cells and consequently in the self-renewal of the intestinal epithelium.
| S-EPMC5131782 | biostudies-literature