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:Annexin A10 (ANXA10) belongs to a family of membrane-bound calcium-dependent phospholipid-binding proteins, but its precise function remains unclear. Further research is required to understand its role in sessile serrated lesions (SSL) and colorectal cancer (CRC). We conducted transcriptome sequencing on pairs of SSL and corresponding normal control (NC) samples. Bioinformatic methods were utilized to assess ANXA10 expression in CRC. We knocked down and overexpressed ANXA10 in CRC cells to examine its effects on cell malignant ability. The effect of ANXA10 on lung metastasis of xenograft tumor cells in nude mice was also assessed. Furthermore, we used quantitative polymerase chain reaction, western blotting, and flow cytometry for reactive oxygen species (ROS), lipid ROS, and intracellular Fe2+ to measure ferroptosis. Immunoblotting and Immunofluorescence staining were used to detect autophagy. We found that ANXA10 was significantly overexpressed in SSL compared to NC. ANXA10 was also highly expressed in BRAF mutant CRCs and was associated with poor prognosis. ANXA10 knockdown reduced the survival, proliferation, and migration ability of CRC cells. Knockdown of ANXA10 inhibited lung metastasis of CRC cells in mice. ANXA10 knockdown increased transferrin receptor (TFRC) protein levels and led to downregulation of GSH/GSSG, increased Fe2+, MDA concentration, and ROS and lipid ROS in cells. Knockdown of ANXA10 inhibited TFRC degradation and was accompanied by an accumulation of autophagic flux and an increase in SQSTM1. Finally, Fer-1 rescued the migration and viability of ANXA10 knockdown cell lines. In brief, the knockdown of ANXA10 induces cellular ferroptosis by inhibiting autophagy-mediated TFRC degradation, thereby inhibiting CRC progression. This study reveals the mechanism of ANXA10 in ferroptosis, suggesting that it may serve as a potential therapeutic target for CRC of the serrated pathway.
| 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.
2024-04-12 | PXD051387 |
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: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: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:TFRC, also known as CD71, regulates the uptake of transferrin-bound iron into cells through receptor-mediated endocytosis. In a patient with a combined immunodeficiency, we identified a homozygous missense mutation in TFRC gene leading to R22W amino acid change in the cytoplasmic tail of the receptor. This mutation impairs the endocytosis of TFRC, which results in profound aberrations in the immune system.
2024-01-31 | GSE243237 | GEO
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:Transcriptional profiling of E2F4 target genes upon overexpression of E2F4 and it cofactors
2010-11-01 | GSE21439 | GEO