Nrf2 activation promotes lung cancer metastasis by blocking degradation of Bach1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA506458 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8236180_1.fastq.gz | Fastqsanger.gz | |||
| SRR8236180_2.fastq.gz | Fastqsanger.gz | |||
| SRR8236190_1.fastq.gz | Fastqsanger.gz | |||
| SRR8236190_2.fastq.gz | Fastqsanger.gz | |||
| SRR8236200_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: The goal of this study is to analyze the transcriptional pathways regulated by Fbxo22 and Keap1 in mouse lung adeno carcinoma cells. Methods: mouse lung adeno carcinoma cells either Keap1 wild type (KP) or mutant (KPK), have been transfected for 3 days with siRNA targeting Fbxo22. Knock down efficiency has been evaluated by western blot (using specific antibody for Fbxo22) and qPCR (using specific oligos for Fbxo22) . Results: The transcriptomic analysis helps us to support our finding that loss of either Keap1 or Fbxo22 induces metastases
2019-06-28 | GSE122836 | GEO
Project description:The transcription factor BACH1 is a transcriptional repressor with a central role regulating oxidative stress and anti-inflammatory pathways, emerging as a promising therapeutic target for multiple conditions, including neurodegenerative disorders, ischemia-reperfusion injuries, sickle cell disease and cancer. In the field of cancer BACH1 has gained significant attention, with BACH1 overexpression correlating with poor prognosis and metastasis across various cancer types; however, despite this increasing relevance of BACH1, no universal pro-metastatic mechanism or transcriptional signature for BACH1 has been identified which is a major limitation for this growing field. To fill this gap, in this study we performed RNA-Seq coupled with ChIP-Seq in BACH1 proficient and deficient lung cancer cells and identified a set of common BACH1 directly regulated genes, which we thoroughly validated in a large panel of cancer cells. This novel lung cancer BACH1 transcriptional signature is highly sensitive and specific to BACH1 perturbations (both genetic and pharmacological) and does not respond to NRF2 modulation, underscoring its specificity. This signature not only represents a robust surrogate for BACH1 activity, but we also provide evidence of its potential value as a tool to i) identify novel BACH1 inhibitors; and ii) provide insights into BACH1’s pro-metastatic role.
2025-08-06 | GSE288626 | GEO
Project description:The transcription factor BACH1 is a transcriptional repressor with a central role regulating oxidative stress and anti-inflammatory pathways, emerging as a promising therapeutic target for multiple conditions, including neurodegenerative disorders, ischemia-reperfusion injuries, sickle cell disease and cancer. In the field of cancer BACH1 has gained significant attention, with BACH1 overexpression correlating with poor prognosis and metastasis across various cancer types; however, despite this increasing relevance of BACH1, no universal pro-metastatic mechanism or transcriptional signature for BACH1 has been identified which is a major limitation for this growing field. To fill this gap, in this study we performed RNA-Seq coupled with ChIP-Seq in BACH1 proficient and deficient lung cancer cells and identified a set of common BACH1 directly regulated genes, which we thoroughly validated in a large panel of cancer cells. This novel lung cancer BACH1 transcriptional signature is highly sensitive and specific to BACH1 perturbations (both genetic and pharmacological) and does not respond to NRF2 modulation, underscoring its specificity. This signature not only represents a robust surrogate for BACH1 activity, but we also provide evidence of its potential value as a tool to i) identify novel BACH1 inhibitors; and ii) provide insights into BACH1’s pro-metastatic role.
2025-08-06 | GSE288627 | GEO
Project description:Quantitative proteomics of mouse derived lung adenocarcinoma cell line KP ( Kras-g12d_p53-/-) compared to an isogenic KPK (KP-sgKeap1) cell line. Cell lysates were prepared in triplicates and individually labeled with TMT reagent, combined, off-line fractionated and concatenated into 40 fractions and subsequently analyzed by LC-MS.
2018-11-23 | MSV000083157 | MassIVE
Project description:Approximately 30% of human lung cancers acquire mutations in either Keap1 or Nfe2l2, resulting in the stabilization of Nrf2, the Nfe2l2 gene product, which controls oxidative homeostasis. Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22. Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme. In mouse models of lung cancers, loss of Keap1 or Fbxo22 induces metastasis in a Bach1-dependent manner. Pharmacological inhibition of Ho1 suppresses metastasis in a Fbxo22-dependent manner. Human metastatic lung cancer display high levels of Ho1 and Bach1. Bach1 transcriptional signature is associated with poor survival and metastasis in lung cancer patients. We propose that Nrf2 activates a metastatic program by inhibiting the heme- and Fbxo22-mediated degradation of Bach1, and that Ho1 inhibitors represent an effective therapeutic strategy to prevent lung cancer metastasis.
| S-EPMC6625921 | biostudies-literature
Project description:BTB and CNC homology 1 (BACH1) is a heme-binding transcription factor repressing the transcription from a subset of MAF recognition elements (MAREs) at low intracellular heme levels. Upon heme binding, BACH1 is released from the MAREs, resulting in increased expression of antioxidant response genes. To systematically address the gene regulatory networks involving BACH1, we combined chromatin immunoprecipitation-sequencing (ChIP-seq) analysis of BACH1 target genes in HEK 293 cells with knock-down of BACH1 using three independent types of small interfering RNAs followed by transcriptome profiling using microarrays. The 59 BACH1 target genes identified by ChIP-seq were found highly enriched in genes showing expression changes after BACH1 knock-down, demonstrating the impact of BACH1 repression on transcription. In addition to known and new BACH1 targets involved in heme degradation (HMOX1, FTL, FTH1, ME1, SLC48A1) and redox regulation (GCLC, GCLM, SLC7A11), we also discovered BACH1 target genes effecting cell cycle and apoptosis pathways (ITPR2, CALM1, SQSTM1, TFE3, EWSR1, CDK6, BCL2L11, MAFG) as well as subcellular transport processes (CLSTN1, PSAP, MAPT, vault RNA). The newly identified impact of BACH1 on genes involved in neurodegenerative processes and proliferation provides an interesting basis for future dissection of BACH1-mediated gene repression in neurodegeneration and virus-induced cancerogenesis. Examination of BACH1 binding in HEK 293T cells by chromatin immunoprecipitation-sequencing (CHIP-seq) with input DNA as control.
2011-05-13 | E-GEOD-28051 | biostudies-arrayexpress
Project description:Bach1 is a known repressor of NRF2 transcription factor which governs oxidative stress during pathophysiology of Parkinson's disease. NRF2 activation in ventral midbrain is associated with protection against oxidative stress induced apoptosis of DA neurons. In this study we hve evaluated the effect of loss of Bach1 fucntion in ventral mid brains.
2021-12-29 | GSE164412 | GEO
Project description:Metastasis is estimated to be responsible for 90% of cancer deaths, and fewer than 10% of patients with metastatic head and neck squamous cell carcinoma (HNSCC) survive beyond 5 years. HNSCC is responsible for upwards of 270,000 global deaths annually, with up to 30% more cases projected annually by 2030. The proto-oncogene MET encodes for the tyrosine kinase receptor c-MET, which is overexpressed in over 80% of human papilloma virus (HPV)-negative HNSCC cases and particularly enriched in metastatic lymph nodes. c-MET is activated by its ligand, hepatocellular growth factor (HGF), and is known to promote cancer cell migration, proliferation, and metastasis through a variety of downstream effectors. Thus far, unfortunately, inhibition of c-MET has shown low efficacy as a single-agent therapy in clinical trials, which indicates a need for further understanding of the mechanisms underlying c-MET-mediated metastasis in HNSCC. We show here that human HNSCC cells upregulate expression of the transcription factor BACH1 through c-MET activation upon HGF treatment. In accordance with previous reports, HGF activation increased expression of epithelial-mesenchymal transition (EMT) markers. Similarly, BACH1 suppression reduced expression of these EMT markers. By pharmacological inhibition of c-MET by FDA-approved capmatinib in combination with hemin treatment to reduce BACH1 expression, migration was reduced compared to either treatment alone in scratch-wound migration assays. Collectively, these data indicate that BACH1 and c-MET are both necessary for the regulation of EMT and migration in HNSCC. Our data suggest the potential for combination therapy targeting both c-MET and BACH1 to reduce HNSCC metastasis.
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Project description:The transcription factor BACH1 is a master regulator of human breast cancer metastasis. Here we use gene expression array analysis to identify and compare the genes regulated by BACH1 depletion in a metastatic human breast cancer cell line. Total RNAs were extracted from vector control 1833 cells or 1833 cells with shBACH mRNA BACH1 depletion. Affymetrix GeneChip Human Gene 1.0 ST Arrays were performed to detail the gene expression and identify the genes regulated by BACH1in metastatic human breast cancer cells.
2013-10-31 | E-GEOD-50226 | biostudies-arrayexpress
Project description:One of the major metabolic responses to counteract aging, inflammation, and various chronic diseases including neurodegeneration, is the so call antioxidant pathway controlled by Nrf2 transcription factor. Nrf2 protein stability is regulated via interaction with the redox sensor Keap1, an adapter protein in Cullin III ubiquitin ligase complex. The search for Nrf2 activators is mainly focused on compounds that either chemically modify sensor thiols in Keap1 or competitively displace Nrf2 from the ubiquitin ligase complex. The latter approach is considered as the most appropriate one for continuous administration without side effects, which are unavoidable in case of non-specific chemical modifiers of Keap1. However, true displacement activators show a significant offset, by many orders of magnitude, when switched from homogeneous assay to cell-based assays. This phenomenon originates, as we show here, from high micromolar intracellular concentrations of Keap1. A guarantee for high specificity of an alkylating Nrf2 activator is its targeted delivery. A transcriptomic analysis for a cell-permeable Nrf2-peptide bearing a fumarate moiety shows the activation of the antioxidant program only, confirming the high specificity of such approach. However, aging-linked neurodegeneration is also known to build-up Bach1, an Nrf2 target gene and competitive transcriptional repressor for Nrf2. Therefore, an ideal combination could be a benign Nrf2 activator and Bach1 inhibitor in one molecule, as represented by the recently developed HPPE. HPPE demonstrates an intersection of the activated antioxidant pathway with the Nrf2 peptide, and, in addition to that, shows a big pool of genes overlapping with the known inhibitors of Bach1 - zinc and tin protoporphyrins. Hence, at present moment, HPPE presents a unique combination of the two desired activities beneficial for age-related neurodegeneration.
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