Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1293892 | ENA |
REPOSITORIES: ENA
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Project description:Cuproptosis, a recently defined copper-dependent cell death, remains largely unexplored in tumor therapies, particularly in breast cancer. Our study demonstrates that triple-negative breast cancer (TNBC) bears a relative elevated copper levels and exhibit resistance to cuproptosis. Mechanistically, cooper activates AKT1 signaling pathway, which inhibits cuproptosis by directly phosphorylating ferredoxin-1 (FDX1), a key regulator involved in cuproptosis. AKT1-mediated FDX1 phosphorylation abrogates FDX1-induced cuproptosis and aerobic respiration, accompanied by promoting glycolysis. Consequently, combination of AKT1 inhibitors MK2206 and the copper ionophore elesclomol (ES) synergistically inhibits TNBC tumorigenesis both in vitro and in vivo. In summary, our findings uncover a critical mechanism underlying TNBC resistance to cuproptosis and propose a potential therapeutic approach for TNBC.
2025-05-07 | PXD058176 | Pride
Project description:Alternative polyadenylation (APA) serves as a critical mechanism for shaping transcriptome diversity and modulating cancer therapeutic resistance. While lactate is a well-established metabolic signal in cancer progression, its role in APA regulation remains unclear. Here, we demonstrate that L-lactate-induced lactylation of NUDT21 drives transcriptomic reprogramming through APA modulation. NUDT21 lactylation enhances its interaction with CPSF6, facilitating CFIm complex formation and inducing 3′ untranslated region (UTR) lengthening of FDX1. Extension of the FDX1 3′ UTR attenuates its protein output, thereby conferring resistance to cuproptosis in esophageal squamous cell carcinoma (ESCC). Furthermore, we identify AARS1 as the lactylation “writer” catalyzing NUDT21 K23 lactylation, and HDAC2 as its enzymatic “eraser”. Clinically, elevated LDHA and NUDT21 levels correlate with reduced FDX1 expression and worse prognosis in ESCC patients. Notably, combined targeting of the lactate-NUDT21-FDX1-cuproptosis axis with the clinical LDHA inhibitor stiripentol and the copper ionophore elesclomol synergistically suppressed tumor growth. Collectively, our work identifies lactylated NUDT21 as a critical factor linking cellular metabolism to APA and proposes a promising therapeutic strategy for ESCC treatment.
2025-05-12 | GSE284372 | GEO
Project description:Single nucleotide polymorphisms in the FTO gene encoding a m6A demthylase are associated with obesity and cancer development. However, the functional role of FTO in the developemnt of progression of hepatocellular carcinoma (HCC) as a proteotypic obesity-associated cancer remains unclear. Here, we have generated mice with hepatic FTO deficiency (FTOL-KO) and subjected them to DEN induced HCC-development. FTOL-KO mice exhibit increased HCC burden. While control mice exhibit a dynamic regulation of FTO upon induction of liver damage, this response is abrogated in mice lacking FTO. Proteomic analyses revealed that liver damage-induced increases in FTO expression promotes m6A-demethylation of CUL4A reducing its protein expression. Functionally, knockdown of CUL4A restores the increased hepatocyte proliferation observed upon loss of FTO. Collectively, our study reveals a protective role for FTO-dependent dynamic m6A mRNA demethylation of CUL4A in the initiation of HCC development.
2020-11-03 | PXD018223 | Pride
Project description:Cuproptosis is characterized by the aggregation of lipoylated components of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. Dysregulation of copper homeostasis and resulting cuproptosis induction is an emerging area of interest for cancer therapy. However, mechanisms of cancer cell evasion of cuproptosis are not well understood. Here, we found that the cuproptosis process is accompanied by activation of the Wnt/β-catenin pathway. Mechanistically, copper binds to PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/β-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed that the β-catenin/TCF4 transcriptional complex directly binds to the promoter region of ATP7B, a protein responsible for the efflux of copper ions from the cell, inducing its expression and reducing intracellular copper accumulation, thereby inhibiting cuproptosis. Knockdown of TCF4 or pharmacological blockade of the Wnt/β-catenin pathway increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and may provide a precision medicine strategy for cancer treatment by selectively inducing cuproptosis
2023-11-21 | GSE248084 | GEO
Project description:Cuproptosis is characterized by the aggregation of lipoylated components of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. Dysregulation of copper homeostasis and resulting cuproptosis induction is an emerging area of interest for cancer therapy. However, mechanisms of cancer cell evasion of cuproptosis are not well understood. Here, we found that the cuproptosis process is accompanied by activation of the Wnt/β-catenin pathway. Mechanistically, copper binds to PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/β-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed that the β-catenin/TCF4 transcriptional complex directly binds to the promoter region of ATP7B, a protein responsible for the efflux of copper ions from the cell, inducing its expression and reducing intracellular copper accumulation, thereby inhibiting cuproptosis. Knockdown of TCF4 or pharmacological blockade of the Wnt/β-catenin pathway increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and may provide a precision medicine strategy for cancer treatment by selectively inducing cuproptosis
2023-11-21 | GSE248083 | GEO
Project description:Fat mass and obesity-associated protein (FTO) can remove both the N6-methyladenosine (m6A) and N6, 2′-O-dimethyladenosine (m6Am) methylation marks that function in multiple aspects of posttranscriptional regulation. Here, we demonstrate that Zbtb48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of Zbtb48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. Zbtb48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which Zbtb48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.
2024-08-26 | GSE228605 | GEO
Project description:Fat mass and obesity-associated protein (FTO) can remove both the N6-methyladenosine (m6A) and N6, 2′-O-dimethyladenosine (m6Am) methylation marks that function in multiple aspects of posttranscriptional regulation. Here, we demonstrate that Zbtb48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of Zbtb48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. Zbtb48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which Zbtb48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.
2024-08-26 | GSE228607 | GEO
Project description:Fat mass and obesity-associated protein (FTO) can remove both the N6-methyladenosine (m6A) and N6, 2′-O-dimethyladenosine (m6Am) methylation marks that function in multiple aspects of posttranscriptional regulation. Here, we demonstrate that Zbtb48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of Zbtb48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. Zbtb48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which Zbtb48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.
2024-08-26 | GSE228606 | GEO
Project description:As an essential micronutrient element in organisms, copper controls a host of fundamental cellular functions. Recently, copper-dependent cell growth and proliferation have been defined as "cuproplasia". Conversely, “cuproptosis” represents copper-dependent cell death, a nonapoptotic manner. So far, a series of copper ionophores have been developed to kill cancer cells. However, the biological response mechanism of copper uptake still lacks systematic analysis. Based on quantitative proteomics, we revealed the crosstalk between copper stress and cuproptosis in cancer cells. Copper stress not only couples with cuproptosis, but also leads to reactive oxygen species (ROS) stress, oxidative damage and cell cycle arrest. In cancer cells, a feedback cytoprotection mechanism involving cuproptosis mediators was discovered. During copper treatment, the activation of glutamine transporters and the loss of Fe-S cluster proteins are the facilitators and results of cuproptosis, respectively. Through copper depletion, glutathione (GSH) blocks the cuproptosis process, rescues the activation of glutamine transporters, and prevents the loss of Fe-S cluster proteins, expect for protecting cancer cells from apoptosis, protein degradation and oxidative damage. Our results are significative for understanding cuproptosis process and developing novel anticancer reagents based on cuproptosis.
2022-11-17 | PXD037278 | Pride
Project description:Copper-related cell death, cuproptosis, involves accumulation of intracellular copper that triggers mitochondrial lipoylated protein aggregation and destabilization of iron–sulfur cluster proteins. Here, glioblastoma (GBM) stem cells (GSCs) displayed resistance to cuproptosis with circadian variation of intracellular copper levels, unlike differentiated GBM cells (DGCs) or neural stem cells (NSCs). CRISPR screening of copper regulators under concurrent treatment with copper ionophore or clock disruption revealed dependency on ATPase Copper Transporting Alpha (ATP7A). Circadian control of copper homeostasis was mediated by core clock transcription factor, Basic helix-loop-helix ARNT-like protein 1 (BMAL1). In turn, ATP7A promoted tumor cell growth through regulation of fatty acid desaturation. Copper levels negatively fed back onto the circadian clock through SQSTM1 (sequestosome 1/p62)-mediated lysosomal degradation of BMAL1. Targeting cuproptosis and circadian clock or fatty acid desaturation generated synergistic anti-tumor effects. Thus, crosstalk between the circadian rhythm and copper sustains GSCs, reshaping fatty acid metabolism and promoting drug resistance.
2025-10-14 | GSE278671 | GEO