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Second-generation BRAF inhibitor Encorafenib resistance is regulated by NCOA4-mediated iron trafficking in the drug-resistant malignant melanoma cells

ABSTRACT: Second-generation BRAF inhibitor Encorafenib resistance is regulated by NCOA4-mediated iron trafficking in the drug-resistant malignant melanoma cells

PROVIDER: PRJNA1192964 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31564962_1.fastq.gz	Fastqsanger.gz
	SRR31564962_2.fastq.gz	Fastqsanger.gz
	SRR31564963_1.fastq.gz	Fastqsanger.gz
	SRR31564963_2.fastq.gz	Fastqsanger.gz
	SRR31564964_1.fastq.gz	Fastqsanger.gz

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Second-generation BRAF inhibitor Encorafenib resistance is regulated by NCOA4-mediated iron trafficking in the drug-resistant malignant melanoma cells

Project description:The current study established the first in vitro Encorafenib resistance protocol in BRAF-mutated malignant melanoma (MM) cells and investigated the resistance-related mechanisms. RNA-Seq results exhibited altered epigenetic regulation of resistance; particularly ferritin family members, ion transport pathways. Then, increased NCOA4, FTH1, and iron levels detected in A375-R suggest that the iron metabolism-related mechanism, such as ferritinophagy, might be triggered, which was supported by TEM and oxidative stress analysis. Iron storage, transport, and ferritinophagy have the promising potential to be targeted for combining with BRAF-targeted therapy to reverse Encorafenib resistance in MM. Moreover, this is the first study evaluating in vitro Encorafenib resistance mechanisms, and we suggest that our findings contribute to improving new drug combinations targeting BRAF and iron metabolism in different MM cells.

2025-01-03 | GSE283251 | GEO

NCOA4

Project description:NCOA4

| PRJNA398076 | ENA

Second-generation BRAF inhibitor Encorafenib resistance is regulated by NCOA4-mediated iron trafficking in the drug-resistant malignant melanoma cells.

Project description:The current study established the first in vitro Encorafenib resistance protocol in BRAF-mutated malignant melanoma (MM) cells and investigated the resistance-related mechanisms. After establishing Encorafenib-resistant A375-MM cells, resistant-related mechanisms were investigated using WST-1, Annexin V, cell cycle, morphological analysis, live-cell, Western blot, RNA-Seq, transmission electron microscopy-(TEM), oxidative stress and iron colorimetric assay. The most resistant group, called A375-R, was determined in the cells treated with a constant dose of 10 nM over 3 months. The viability, apoptosis, and G0/G1 arrest reflected the acquired chemoresistance. Autophagic Beclin and LC3 proteins, and AKT signaling increased in the A375-R. RNA-Seq results also exhibited altered epigenetic regulation of resistance; particularly ferritin family members, ion transport pathways. Then, increased NCOA4, FTH1, and iron levels detected in A375-R suggest that the iron metabolism-related mechanism, such as ferritinophagy, might be triggered, which was supported by TEM and oxidative stress analysis. Iron storage, transport, and ferritinophagy have the promising potential to be targeted for combining with BRAF-targeted therapy to reverse Encorafenib resistance in MM. Moreover, this is the first study evaluating in vitro Encorafenib resistance mechanisms, and we suggest that our findings contribute to improving new drug combinations targeting BRAF and iron metabolism in different MM cells.

| S-EPMC11742906 | biostudies-literature

Effect of iron depletion on gene expression of NCOA4-deficient and control HT22 hippocampal neuron cells

Project description:To determine the physiological roles of NCOA4 and NCOA4-mediated ferritinophagy in hippocampal neurons, NCOA4 was depleted using siRNA and desferrioxamine (DFO; 100 µM, 24 h) was added to restrict iron availability. Cells were treated for NCOA4 depletion, iron restriction, or both, and then the transcriptome profiles acquired from RNA-seq were compared with those of control (scramble siRNA-treated) cells.

2022-12-30 | GSE211931 | GEO

Transcriptome profiling of human erythroblast cells knocking down NCOA4

Project description:Purpose: Knocking down NCOA4 disrupted Thyroid hormone receptor beta agonist,GC-1, mediated terminal human erythroblast differentiation. Therefore, we conducted RNA-seq to profile the transcriptome changes in NCOA4 knocked down human erythroblasts.. Methods: Human CD34+ cells were transduced by lentiviruses encoding shRNAs targeting either LacZ (control) or NCOA4 atday 1 of culture. At day 14, cells were switched to terminal differentiation medium. Results: Using an optimized data analysis workflow, we have identified an ensemble of genes whose expression are discrupted by NCOA4 knockdown. Conclusions: There is a significant correlation between the degree of GC-1-mediated gene activation and the degree of NCOA4 knockdown-mediated gene repression.

2017-09-06 | GSE102582 | GEO

NCOA4-mediated ferritinophagy is a pancreatic cancer dependency via maintenance of iron bioavailability for iron-sulfur cluster proteins

Project description:Oncogenic KRAS rewires pancreatic ductal adenocarcinoma (PDAC) metabolism to promote dependence on autophagy and iron metabolism. NCOA4-mediated ferritinophagy links autophagy and iron metabolism as NCOA4 selectively targets ferritin, the cellular iron storage complex, via autophagy to the lysosome for ferritin degradation and release of iron for utilization. Using patient-derived and genetically engineered murine models of PDAC we now demonstrate that ferritinophagy is upregulated in PDAC to sustain iron availability thereby promoting PDAC progression. PDAC global quantitative proteomics reveals that ferritinophagy fuels iron-sulfur cluster synthesis to support mitochondrial homeostasis. Targeting NCOA4 leads to tumor growth delay and prolonged survival but with development of compensatory iron acquisition pathways. Finally, a ferritinophagy gain-of-function PDAC murine model demonstrates worse survival, and an elevated ferritinophagy expression signature predicts for worse overall survival in human PDAC patients. Together, our data define NCOA4-mediated ferritinophagy as a therapeutic target in PDAC and reveal that maintenance of cellular iron homeostasis is a critical cell autonomous function of PDAC autophagy.

2022-08-17 | PXD033356 | Pride

Effect of NCOA4-depletion on the transcriptome profile of J774 mouse macrophage cells

Project description:To determine the physiological roles of NCOA4 and ferritinophagy in macrophages, NCOA4 was depleted via liposome-mediated siRNA delivery into cells. Cells were treated with siRNA for NCOA4 depletion and then the transcriptome profiles acquired from RNA-seq were compared with those of control (scramble siRNA-treated) cells.

2022-09-30 | GSE212772 | GEO

Ncoa4-mediated ferritinophagy as a dependence in Tet2-deficient hematopoiesis

Project description:TET2 is among the most commonly mutated genes in both clonal hematopoiesis and myeloid malignancies, thus, the ability to identify selective dependencies in TET2 deficient cells has broad translational significance. Here, we identify regulators of Tet2 knockout (KO) hematopoietic stem and progenitor cell (HSPC) expansion using an in vivo CRISPR-Cas9 KO screen, in which nucleotide barcoding enabled large-scale clonal tracing of Tet2 deficient HSPCs in a physiological setting. Our screen identified candidate genes, including Ncoa4, that are selectively required for Tet2 KO clonal outgrowth compared to wild-type (WT). Ncoa4 targets ferritin for lysosomal degradation (ferritinophagy), maintaining intracellular iron homeostasis by releasing labile iron (Fe2+) in response to cellular demands. In Tet2-deficient HSPCs, increased mitochondrial ATP production correlates with increased cellular iron requirements, and in turn, promotes Ncoa4-dependent ferritinophagy. Restricting iron availability reduces Tet2 KO stem cell numbers, revealing a dependency in TET2-mutated myeloid neoplasms.

2025-06-01 | GSE289732 | GEO

HDX-MS data on bRaf, bRaf/Cdc37 and bRaf/Cdc37/Hsp90 protein complexes

Project description:HDX-MS data on bRaf, bRaf/Cdc37 and bRaf/Cdc37/Hsp90 protein complexes

2022-01-04 | MSV000088635 | MassIVE

BEACON treatment with cetuximab every second week - cetuximab given every second week with encorafenib in prior treated patients with spred bowel cancer with a specific (BRAF) mutation. A drug trial.

Project description:Primary objectives: The purpose of this study is to evaluate the efficacy and tolerability of cetuximab every second week together with encorafenib in patients with pre-treated, metastatic BRAF-mutated colorectal adenocarcinoma.Primary objective is 2 months Progression Free Survival (PFS) rate. Primary endpoints: 2 months PFS rate

| 2540537 | ecrin-mdr-crc

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