N-acetylcysteine and Vitamin C stimulate MYC binding to EGR1 and selectively stimulate apoptosis in B cell lymphoma
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ABSTRACT:
PROVIDER: PRJNA821686 | ENA |
REPOSITORIES: ENA
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Project description:Refractory and relapsed B cell lymphomas are often driven by MYC, a difficult-to-target oncogene due to its central role in normal transcription. Here we report that N-acetylcysteine (NAC) and vitamin C (VitC)—in doses that reduce reactive oxygen species levels levels—trigger apoptosis in human B lymphoma cells with high MYC expression. Intraperitoneal NAC and VitC injections dose-dependently reduced tumor growth in xenograft experiments, and combined NAC/VitC administration stopped tumor growth. Knockdown of MYC restored tumor growth in the presence of NAC and VitC and switching-on MYC expression in B cells rendered them sensitive to the compounds. The compounds stimulated MYC binding to Early growth response protein 1 (EGR1)—an interaction found to require Cys132 of MYC—which reduced MYC binding to promotors of cell cycle genes and increased binding to apoptotic genes; and thus, switched MYC’s transcriptional output from cell cycle to apoptosis gene expression. Short-term combined NAC/VitC administration into λMYC transgenic mice, an endogenous mouse model of B cell lymphoma, after tumor onset increased survival fourfold; and life-long oral administration of NAC and VitC stimulated apoptosis and reduced B cell progenitors in the spleen and measurably increased survival. The results provide a rationale with mechanistic understanding for evaluating the therapeutic efficacy of NAC and VitC in patients with MYC-driven B cell lymphoma.
2023-08-01 | GSE199843 | GEO
Project description:In this study,we demonstrated the transcription factor EGR1 is activated by TCM YYJD and such activation mediated YYJD-induced apoptosis in lung cancer cells and provided a novel insight to understand the anti-tumor mechanism of Chinese herb YYJD.
2018-11-01 | E-MTAB-7236 | biostudies-arrayexpress
Project description:Human bone marrow stromal cells (BMSCs) are key elements of the hematopoietic environment and they play a central role in bone and bone marrow physiology. However, how key BMSC functions are regulated is largely unknown. We analyzed the role of the immediate early response transcription factor EGR1 as key BMSC regulator and found that EGR1 was highly expressed in prospectively-isolated primary BMSCs, downregulated upon culture, and lower in non-CFU-F-containing CD45neg BM cells. Furthermore, EGR1 expression was lower in proliferative regenerating adult and fetal primary cells compared to adult steady-state BMSCs. Accordingly, EGR1 overexpression markedly decreased BMSC proliferation but considerably improved hematopoietic stroma support function as indicated by an increased production of transplantable CD34+CD90+ hematopoietic stem cells in expansion co-cultures. The improvement of BMSC stroma support function was mediated by increased expression of hematopoietic supporting genes, such as VCAM1 and CCL28. On the other hand, EGR1 knockdown increased ROS-mediated BMSC proliferation, and clearly reduced BMSC hematopoietic stroma support potential. These findings thus show that EGR1 is a key BMSC transcription factor with a dual role in regulating proliferation and hematopoietic stroma support function that is controlling a genetic program to coordinate the specific functions of BMSC in their different biological contexts.
2019-06-27 | PXD011767 | Pride
Project description:In this study,we demonstrated the transcription factor EGR1 is activated by TCM YYJD and such activation mediated YYJD-induced apoptosis in lung cancer cells and provided a novel insight to understand the anti-tumor mechanism of Chinese herb YYJD.
2018-11-01 | E-MTAB-7237 | biostudies-arrayexpress
Project description:To gain insight into the function of DNA-PKcs within immune cells, we performed a quantitative phosphoproteomic screen in T cells to identify first order phosphorylation targets of DNA-PKcs. Results indicate that DNA-PKcs phosphorylates the transcription factor Egr1 (early growth response protein 1) at S301. Expression of Egr1 is induced early upon T cell activation and dictates T cell response by modulating expression of cytokines and key costimulatory molecules. Mutation of serine 301 to alanine via CRISPR-Cas9 resulted in increased proteasomal degradation of Egr1 and a decrease in Egr1-dependent transcription of IL2 (interleukin-2) in activated T cells. Our findings identify DNA-PKcs as a critical intermediary link between T cell activation and T cell fate and a novel phosphosite involved in regulating Egr1 activity.
2021-12-21 | PXD026352 | Pride
Project description:Some chemotherapy drugs influence the formation of stress granules (SGs), cytoplasmic RNA foci involved in stress response pathways. The exact role of SGs in promoting cell survival or apoptosis needs further clarification. The chemotherapy drug lomustine induces SG formation by activating the eIF2α kinase HRI (EIF2AK1). We performed a DNA microarray transcriptome analysis to identify genes affected by lomustine-induced stress and to explore the role of SGs. Our findings show that lomustine specifically regulates the expression of the pro-apoptotic EGR1 gene. The presence of EGR1 mRNA in SGs correlates with reduced translation of EGR1 mRNA. Lomustine likely sequesters EGR1 mRNA into SGs, preventing its ribosomal translation and thereby limiting apoptosis. This supports a model where SGs selectively sequester specific mRNAs in response to stress, modulate their translation, and thus determine the fate of stressed cells.
2024-06-20 | GSE269691 | GEO
Project description:EGR1-mediated ibrutinib resistance
| PRJNA925145 | ENA
Project description:Therapy-related myeloid neoplasms (t-MN) share many similarities with AML de novo in the elderly. One common factor is that they arise in the setting of chronic inflammation, likely due to advanced age or chemotherapy-induced senescence. Here, we examined the impact of haploinsufficient loss of the del(5q) tumor suppressor gene, EGR1, commonly deleted in high-risk MNs. In mice, under the exogenous inflammatory stress of either serial transplant or successive doses of the alkylating agent ENU, Egr1-haploinsufficient hematopoietic stem cells (HSCs) exhibit a clonal advantage. Complete loss of EGR1 function is incompatible with transformation; mutations of EGR1 are rare and are not observed in the remaining allele in del(5q) patients and complete knockout of Egr1 in mice leads to HSC exhaustion. Using chromatin immunoprecipitation sequencing (ChIP-seq), we identify EGR1 binding sites in human CD34+ cord blood-derived stem and progenitor cells (HSPCs) and show that EGR1 binds genes critical for stem cell differentiation, inflammatory signaling, and the DNA damage response. Notably, in the chromosome 5 sequences frequently deleted in patients, there is a significant enrichment of innate and inflammatory genes, which may confer a fitness advantage in an inflammatory environment. Short hairpin RNA (shRNA) mediated silencing of EGR1 biases HSPCs towards a self-renewal transcriptional signature. In the absence of EGR1, cells upregulate MYC-driven proliferative signals, downregulate CDKN1A (p21), disrupt the DNA damage response, and downregulate inflammation - adaptations anticipated to confer a relative fitness advantage for stem cells especially in an environment of chronic inflammation.
2022-09-01 | GSE184931 | GEO
Project description:We established two representative ABC DLBCL cell lines (TMD8 and OCI-Ly10) with ibrutinib resistance by gradually increasing the concentration of ibrutinib during passage in culture. RNA-seq analysis demonstrated that the BCR pathway gene signature is enriched in resistant cell lines when compared to parental cells. The most upregulated gene is EGR1, a transcription factor that activates multiple oncogenic pathways including MYC and E2F. Elevated EGR1 expression is also observed in ibrutinib-resistant primary mantle cell lymphoma cells when treated with ibrutinib. Using multiple metabolic and genetic approaches, we discovered that overexpression of EGR1 causes metabolic reprogramming to oxidative phosphorylation (OXPHOS) and ibrutinib resistance. Mechanistically, EGR1 mediates metabolic reprogramming through transcriptional activation of PDP1, a phosphatase that dephosphorylates and activates the E1 component of the large pyruvate dehydrogenase complex. Therefore, EGR1-mediated PDP1 activation accelerates intracellular ATP production via the mitochondrial tricarboxylic acid (TCA) cycle, leading to sufficient energy to enhance the proliferation and survival of ibrutinib-resistant lymphoma cells. Finally, we demonstrate that targeting OXPHOS with IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in patient-derived xenograft mouse models.
2023-12-06 | GSE223150 | GEO
Project description:Egr1 regulates genes involved in cholesterol biosynthesis in liver. ChIP-chip assays were performed on H4IIE liver cells that were either treated or untreated with insulin for one hour. This experiment includes a custom ChIP-chip design incorporating many genes that are dynamically regulated by insulin signaling. The Egr1 antibody used was from Santa Cruz sc-189. Egr1 ChIP samples from untreated and 1h insulin treated cells were hybridized.
2011-07-22 | E-GEOD-30823 | biostudies-arrayexpress