Loss of MTCH2 induces E2F4/TFRC-mediated ferroptosis in colorectal cancer
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ABSTRACT:
PROVIDER: PRJNA1161158 | ENA |
REPOSITORIES: ENA
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Project description:Ferroptosis is a specific type of lipid peroxide-mediated cell death which is crucial in tumor suppression. While the mitochondrial carrier homolog 2 (MTCH2) is implicated in lipid homeostasis and mitochondrial metabolism, its role in ferroptosis and colorectal cancer (CRC) remains uncharacterized. Here, we identified MTCH2 as a crucial regulator of ferroptosis in CRC progression. Clinically, high expression of MTCH2 in CRC tissues predicted poor prognosis. Functionally, loss of MTCH2 inhibited azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal tumorigenesis in intestine-conditional Mtch2 knockout (Mtch2cKO) mice and led to accumulation of ferrous ion and enhanced ferroptosis of CRC in vitro and in vivo. Mechanistically, MTCH2 deficiency promoted the proteasome-dependent ubiquitination of E2F4 and attenuated transcriptional inhibition of transferrin receptor (TFRC) by E2F4, ultimately facilitating TFRC-mediated ferroptosis in CRC cells. Taken together, our study reveals the mechanism of MTCH2 deficiency induced ferroptosis to inhibit the progression of CRC, and supports a potential therapeutic strategy targeting the MTCH2/E2F4/TFRC signaling axis in CRC patients with liver metastasis.
2025-08-01 | GSE277185 | GEO
Project description: Not available
| S-EPMC10477278 | biostudies-literature
Project description:Older livers are more prone to hepatic ischaemia/reperfusion injury (HIRI), which severely limits their utilization in liver transplantation (LT); however, the potential mechanism remains unclear. Here, we demonstrated older livers exhibit a higher degree of ferroptosis during HIRI. Inhibiting ferroptosis significantly attenuated older HIRI. Mass spectrometry revealed fat mass and obesity-associated gene (FTO) was downregulated in older livers, especially during HIRI. Overexpressing FTO ameliorated older HIRI by inhibiting ferroptosis. Mechanistically, ACSL4 and TFRC, two key positive contributors of ferroptosis, were targets of FTO. The mitigating effect of FTO on older HIRI required the inhibition of Acsl4 and Tfrc mRNA stability in a m6A-dependent manner. Furthermore, we demonstrated nicotinamide mononucleotide (NMN) could upregulate FTO demethylase activity to suppress ferroptosis and attenuate older HIRI. Collectively, these findings revealed an FTO-ACSL4/TFRC regulatory pathway that contributes to the pathogenesis of older HIRI, providing insight into the clinical translation of strategies related to the demethylase activity of FTO in order to improve graft function after older donor LT.
| PXD051387 |
Project description:E2F transcription factors are central regulators of cell cycle progression and cell fate decisions in mammalian cells. E2F4 is a transcriptional repressor implicated in cell cycle arrest and whose repressive activity depends on its interaction with members of the RB family. E2F4 often represents the predominant E2F activity in cells. Here we show that E2F4 is important for the proliferation and the survival of mouse embryonic stem cells. In these cells, E2F4 acts in part as a transcriptional activator that promotes the expression of cell cycle genes. Importantly, this role for E2F4 is completely independent of the RB family. Accordingly, an unbiased analysis of the E2F4 interactome shows that E2F4 functionally interacts with chromatin regulators associated with gene activation in RB family-mutant cells. Taken together, our findings uncover a non-canonical role for E2F4 that reveal novel insights into the biology of rapidly dividing cell types.
2019-04-26 | PXD008796 | Pride
Project description:We investigated the ability of transferrin receptor1 (TfRc) knockout cells to populate different domains of the developing kidney by using a chimeric approach. The TfRc cells developed into all segments of the developing nephron, but there was a relative exclusion from the ureteric bud and a positive bias towards the stromal compartment. Here we conducted a microarray analysis of differential gene expression between TfRc deficient and wild type (wt) cells in chimeric embryonic kidneys derived from embryos created by blastocyst injection of wt blastocysts with TfRc-/- green fluorescent protein-expressing (GFP+) embryonic stem cells. Keywords: cell type comparison, genetic modification, iron signaling
2008-08-01 | GSE7396 | GEO
Project description:E2F4 wild and knockout type neurospheres from E12.5 forebrain. E2F4 transcription factor regulates the expression of the genes which are required for neural stem cell expansion in the developing mouse brain. The results of microarray analysis will help to identify the signaling pathways affected by E2F4 deletion and refine the neural stem cell regulatory mechanism. Keywords: other
2008-02-13 | GSE10401 | GEO
Project description:Transcriptional profiling of E2F4 target genes upon overexpression of E2F4 and it cofactors 4 conditions; E2F4 overexpression vs mock, E2F4 and DP-1 overexpression vs mock, E2F4 and RBL2 overexpression vs mock, E2F4, DP-1, and RBL2 overexpression vs mock. 2 or 4 replicates for each experimental conditions
2010-11-01 | E-GEOD-21439 | biostudies-arrayexpress
Project description:We have used primary MEFs derived from wild type and E2F4 null mice growing asynchrounously in serum to generate a signature for E2F4 pathway activation. 10 wild type and 10 E2F4 null samples were each assayed using the Affymetrics Mouse Genome 430A 2.0 array. Keywords: Primary MEFs from wild type and E2F4 null mice
2008-07-11 | GSE11039 | GEO
Project description:We discovered, through untargeted metabolomics, that creatine promotes ferroptosis in colorectal cancer. Our study identifies ERK2 as a creatine sensor that mediates active FSP1 and ferroptosis resistance, and highlights the potential of targeting tumor SLC6A8 for cancer treatment.
2025-09-05 | GSE285466 | GEO
Project description:Background: Pulmonary endothelial cell (EC) activation is a key factor in acute respiratory distress syndrome (ARDS). In sepsis, increased glycolysis leads to lactate buildup, which induces lysine lactylation (Kla) on histones and other proteins. However, the role of protein lactylation in EC dysfunction during sepsis-induced ARDS remains unclear. Methods: Integrative lactylome and proteome analysis was performed to identify the global lactylome profiling in lung tissues of septic mice. Cut&Tag analysis were used to identify the transcriptional targets of histone H3 lysine 14 lactylation (H3K14la) in ECs. Results: Septic mice exhibited elevated levels of lactate and H3K14la in lung tissues, particularly in pulmonary ECs. Suppressing glycolysis reduced both H3K14la and EC activation, suggesting a link between glycolysis and lactylation. Moreover, H3K14la was found to be enriched at promoter regions of ferroptosis-related genes such as transferrin receptor (TFRC) and solute carrier family 40 member 1 (SLC40A1), which contributed to EC activation and lung injury under septic conditions. Conclusions: We for the first time reported the role of lactate-dependent H3K14 lactylation in regulating EC ferroptosis to promote vascular dysfunction during sepsis-induced lung injury. Our findings suggest that manipulation of glycolysis/H3K14la/ferroptosis axis may provide novel therapeutic approaches for sepsis-associated ARDS.
2025-05-07 | PXD056805 | Pride