TET1-mediated DNA hydroxymethylation controlling ferroptosis resistance in cancer [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE240524 | GEO | 2025/12/05
REPOSITORIES: GEO
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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:KRAS mutation activates multiple intracellular signalling pathways, leading to tumour development and progression. However, whether KRAS mutations are involved in regulating ferroptosis in cancer and the underlying mechanism remains unclear. Here, we constructed stable KRASWT and KRASG12D-mutant cell lines by transfecting wild-type (WT) or G12D plasmids into original KRAS WT cells and detected their cell viability under the treatment of ferroptosis inducer RSL3 or erastin. We found compared with WT cells, KRASG12D-mutated pancreatic and colorectal cancer cells presented greater viability and less cell death, along with lower levels of lipid peroxidation (LPO) and fewer damaged mitochondria, suggesting that the G12D mutation confers resistance to ferroptosis. Moreover, we found that KRASG12D mutated cancer cells demonstrated increased glycolysis and elevated lactate production, which was dependent on MEK-ERK-mediated L-lactate dehydrogenase A (LDHA) phosphorylation. Importantly, lactate supplementation in WT cells also resulted in ferroptosis resistance, indicating that G12D mutation-induced resistance to ferroptosis may be linked to lactate production. Mechanistically, G12D mutation-derived lactate accumulation induces Glutamate-cysteine ligase modifier (GCLM) lactylation, a process catalysed by Acetyl-CoA Acetyltransferase 2 (ACAT2). Inhibition of GCLM lactylation either through the mutation of the lactylation site or by knockdown of ACAT2 diminished the enzymatic activity of Glutamate-cysteine ligase (GCL) and suppressed Glutathione (GSH) synthesis. Ultimately, we found that ACAT2 knockdown can overcomes ferroptosis resistance in G12D-mutated cancer models in vivo. Thus, our study reveals a novel role for the G12D mutation in regulating GCLM lactylation and ferroptosis. Targeting GCLM lactylation may represent a promising strategy for overcoming ferroptosis resistance.
2025-05-07 | PXD062451 | Pride
Project description:TET1, the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), was first identified as a partner gene in MLL-rearranged leukemia, but its definitive pathological role in leukemia is unclear. The down-regulation of all three TET genes and loss-of-function mutations of TET2 have been frequently observed in various cancers, and it was thought that they all play tumor-suppressor roles in tumorigenesis. Here we show that TET1 is likely a direct target of MLL and significantly up-regulated in MLL-rearranged leukemia, associated with an increased level of 5hmC. Our further in vitro and in vivo studies demonstrate that Tet1 plays an indispensable oncogenic role in MLL-rearranged leukemia, through cooperating with MLL fusion proteins in regulating their co-targets including the Hoxa/Meis1/Pbx3/Flt3 genes. Our data delineate a MLL-fusion/Tet1/Hoxa/Meis1/Pbx3/Flt3 signaling axis in MLL-rearranged leukemia, and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.
2015-12-14 | GSE42990 | GEO
Project description:TET1, the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), was first identified as a partner gene in MLL-rearranged leukemia, but its definitive pathological role in leukemia is unclear. The down-regulation of all three TET genes and loss-of-function mutations of TET2 have been frequently observed in various cancers, and it was thought that they all play tumor-suppressor roles in tumorigenesis. Here we show that TET1 is likely a direct target of MLL and significantly up-regulated in MLL-rearranged leukemia, associated with an increased level of 5hmC. Our further in vitro and in vivo studies demonstrate that Tet1 plays an indispensable oncogenic role in MLL-rearranged leukemia, through cooperating with MLL fusion proteins in regulating their co-targets including the Hoxa/Meis1/Pbx3/Flt3 genes. Our data delineate a MLL-fusion/Tet1/Hoxa/Meis1/Pbx3/Flt3 signaling axis in MLL-rearranged leukemia, and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease. We report genome-wide 5hmC enrichment profiles and RNA-Seq gene expression in MLL-AF9 transformed and control mouse bone marrow mononuclear cells. These 5hmC profiles are derived from selctive chemical labeling and enrichment of 5hmC containing genomic DNA fragments, while the RNA-Seq expression profiles are generated from polyA enriched RNA
2015-12-14 | E-GEOD-42990 | biostudies-arrayexpress
Project description:We conducted a proteomic interactome analysis of well-known regulators of ferroptosis, ACSL4, LPCAT3, ALOX12, ALOX15, PEBP1, NCOA4, GCH1, FSP1, DHODH, SLC7A11, GCLC, GCLM, GSS, and GPX4. Take LPCAT3 as an example, we uncovered an opposing role of its binding protein CEPT1 in suppressing ferroptosis.
2024-10-17 | PXD035146 | Pride
Project description:Surveillance of DNA methylation in mammals is critical for genome stability and epigenetic regulation. The discovery of the ten-eleven translocation (TET) proteins catalyzing the oxidation from 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) revolutionized the understanding of DNA methylation dynamics. Interestingly, in recent years evidence accumulated that TET1 also harbours non-catalytic functions. However, the role and mechanism of TET1 DNA demethylation independent functions still remain poorly understood. Here, we use genome engineering and quantitative multi-omics approaches to dissect the non-catalytic role of TET1. Strikingly, we find that the majority of transcriptional regulation depends on non-catalytic functions of TET1. To gain insights into possible mechanisms by which TET1 regulates transcription independent of DNA demethylation, we asked if the loss of TET1 is accompanied by changes in the histone modificaiton landscape. To this end, we compared the relative abundances of core histone modifications between Tet1 KO, Tet1 CM and WT mESCs using quantitative LC-MS/MS analysis. Surprisingly, we observed a profound global reduction of pH4Kac and H4K20me3 as well as H3K27me3 in Tet1 KO mESC. Vice versa, the monomethylation states of the latter two residues, H3K27me1 and H4K20me1 were significantly increased in Tet1 KO. Similar to the results from the transcriptome data, most of these changes were specific to Tet1 KO cells.
2022-08-11 | PXD028566 | Pride
Project description:Precise regulation of DNA methylation in mammals is critical for genome stability and epigenetic regulation. The discovery of the ten-eleven translocation (TET) proteins catalyzing the oxidation from 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) revolutionized the perspective on the complexity and regulation of DNA modifications. Despite accumulating knowledge about the role of TET1, it remains unclear to what extent these can be attributed to its catalytic activity. Here, we use genome engineering and quantitative multi-omics approaches to dissect the role and mechanism of TET1 in mESCs. Our study identifies TET1 as an essential interaction hub for multiple chromatin modifying complexes and as a global regulator of histone modifications. Strikingly, we find that the majority of transcriptional regulation depends on non-catalytic functions of TET1. Moreover, we show that the establishment of H3K9me3 and H4K20me3 at ERV1, ERVK, and ERVL is mediated by TET1 independent of DNA demethylation. We provide evidence that repression of endogenous retroviruses depends on the interaction between TET1 and SIN3A. In summary, we demonstrate that the non-catalytic functions of TET1 are critical for regulation of gene expression and the silencing of endogenous retroviruses in mESCs.
2022-08-31 | PXD028850 | Pride
Project description:TET1, TET2 and TET3 are DNA demethylases with critical roles during early embryonic development and cell differentiation. To assess the contributions of TET proteins to cell function during early development, single and compound knockouts of Tet genes in mouse pluripotent embryonic stem cells (ESCs) were generated. ESCs lacking all alleles of Tet1 and Tet2, or all alleles of Tet1, Tet2 and Tet3 form epiblast-like cells and epiblast stem cells in culture, indicating that TET proteins are not required to transit between naïve, formative and primed pluripotency. Moreover, in differentiation protocols, ESCs with double-knockouts of Tet1 and Tet2 or triple-knockouts of Tet1, Tet2 and Tet3 do not differentiate normally , fail to activate somatic gene expression and retain expression of pluripotency transcription factors. Therefore, TET1 and TET2, but not TET3 act redundantly to facilitate somatic differentiation. Importantly, ESCs with double knockouts of Tet1 and Tet2, or triple knockouts of Tet1, Tet2 and Tet3 cells do differentiate into primordial germ cell-like cells (PGCLCs). Furthermore, PGCLC differentiation of Tet1, Tet2 double knockouts, or Tet1, Tet2, Tet3 triple knockouts occurs with high efficiency in the presence or absence of PGC-promoting cytokines. Moreover, acquisition of a PGCLC transcriptional programme occurs more rapidly in the absence of TET proteins. These results establish TET proteins as key regulators enabling epiblast cells to choose between somatic and germline fates. The functions of Tet1 and Tet2, but not Tet3 are required to enable epiblast cells to undergo somatic differentiation and in the absence of TET protein function, epiblast cell differentiation defaults to the germline.
2025-08-01 | GSE273732 | GEO
Project description:Epigenetic pathways that regulate DNA methylation and chromatin modifications are frequently found to be dysregulated in human cancers. The TET methylcytosine dioxygenase 1 (TET1) enzyme is an important regulator of hydroxymethylcytosine (5hmC) in embryonic stem cells, neural progenitors,adult cells and reprogrammed cells. Decreased expression of TET proteins and loss of 5hmC has been reported in many tumors, suggesting a critical role for the maintenance of this epigenetic modification in normal cellular function. However, loss of TET1 function in the etiology of cancer has not been directly investigated. Here, we show that deletion of the Tet1 gene promotes the development of B cell lymphoma. Tet1 is required for maintaining normal levels of 5hmC, preventing aberrant DNA hypermethylation and for the regulation of transcriptional programs involved in B-cell lineage specification, chromosome maintenance, and DNA repair. Progenitor B cells in the absence of Tet1 accumulate DNA damage and whole-exome sequencing of Tet1-deficient tumors revealed a high correlation of mutations with those most frequently found in Non-Hodgkin B cell lymphoma (B-NHL) patients. In addition, we show that the TET1 gene is deleted, hypermethylated and transcriptionally silenced in B-NHL patients. These findings provide the first in vivo evidence of TET1 function as a tumor suppressor of hematopoietic malignancy. We did hydroxymethylation tests for two wild type mice and two Tet1 knockout mice.
2015-04-12 | E-GEOD-65895 | biostudies-arrayexpress