Nrf2 and HIF1α merge to arsenic-induced metabolic reprogramming and formation of the cancer stem-like cells.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA608476 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11173390.fastq.gz | Fastqsanger.gz | |||
| SRR11173391.fastq.gz | Fastqsanger.gz | |||
| SRR11173392.fastq.gz | Fastqsanger.gz | |||
| SRR11173393.fastq.gz | Fastqsanger.gz | |||
| SRR11173394.fastq.gz | Fastqsanger.gz |
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Project description:Arsenic (iAs) induces generation of the cancer stem-like cells (CSCs) through Nrf2-dependent HIF1α activation, and the subsequent metabolic reprogramming from mitochondrial oxdaive phosphorylation to glycolysis in epithelial cells.
2020-02-25 | GSE145834 | GEO
Project description:In this report, we demonstrated that inorganic arsenic (iAs) induces generation of the cancer stem-like cells (CSCs) through Nrf2-dependent HIF1α activation, and the subsequent metabolic reprogramming from mitochondrial oxidative phosphorylation to glycolysis in epithelial cells. Methods: Genome-wide ChIP-seq analysis was performed to investigate the global binding of Nrf2 and/or HIF1α on the genome in the cells treated with iAs. Both untargeted metabolomics and UDP-13C-glucose flux were applied to determine metabolic reprogramming in the iAs-induced CSCs. The role of Nrf2 on iAs-induced HIF1α and other stemness gene expression was validated by lentiviral transfection of Nrf2 inhibitor Keap1 and CRISPR-Cas9-mediated Nrf2 gene knockout, respectively. Results: The CSCs induced by iAs exhibit a diminished mitochondrial oxidative phosphorylation and an enhanced glycolysis that is actively shunted to the hexosamine biosynthetic pathway (HBP) and serine/glycine pathway. ChIP-seq data revealed that treatment of the cells with iAs amplified Nrf2 enrichment peaks in intergenic region, promoter and gene body. In contrast, a shift of the HIF1α peaks from distal intergenic region to gene promoter and the first exon was noted. Both Nrf2 and HIF1α are responsible for the iAs-induced expression of the glycolytic genes and the genes important for the stemness of the CSCs. Intriguingly, we also discovered a mutual transcriptional regulation between Nrf2 and HIF1α. Inhibition of Nrf2 by lentiviral infection of Keap1, or knockout of Nrf2 by CRISPR-Cas9 gene editing, not only blocked iAs-induced HIF1α activation, but reduced the expression of the key stemness genes for the formation of CSCs also. Conclusion: We demonstrated that Nrf2 activation is an initiating signal for iAs-induced HIF1α activation, and Nrf2 and HIF1α played a concerted role on inducing metabolic reprogramming and the CSCs.
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Project description:Emerging evidence suggests that Nrf2 plays a pro-carcinogenic role in various cancers. Our previous study showed that arsenic-induced Nrf2 activation promotes metabolic reprogramming and cancer stem-like cell formation. Here, we identify KLF4, a key pluripotency factor, as a direct transcriptional target of Nrf2 in arsenic-exposed human bronchial epithelial cells. ChIP-seq revealed multiple Nrf2 binding peaks at the KLF4 gene locus, co-localizing with the enhancer markers H3K4me1 and H3K27Ac. Nrf2 knockout reduced KLF4 expression and decreased enhancer marker enrichment, alongside a genome-wide reduction in KLF4 binding in arsenic-treated BEAS-2B cells. In BEAS-2B cells with functional Nrf2, arsenic treatment significantly increased KLF4 binding on genes involved in several oncogenic pathways, including STAT3, SOX2, Nrf2, cell growth, Hedgehog, and epithelial-to-mesenchymal transition (EMT). We also found that KLF4 participates in a self-regulating feedback loop in response to arsenic-induced Nrf2 signaling. Co-occupancy of Nrf2 and KLF4 is crucial for establishing active enhancers, suggesting that Nrf2’s oncogenic effects are, at least in part, mediated by Nrf2-dependent self-amplification of KLF4 expression and function. Thus, co-targeting Nrf2 and KLF4 may represent a promising therapeutic strategy for eliminating cancer stem-like cells.
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Project description:As3+ will disrupt the tumor suppressor-like activity of AHR, either through preventing the formation of repressive complexes or the binding of the repressive complexes to these oncogenic genes. Meanwhile, the reduced AHR binding to the DNA may also enhance the nuclear translocation and transcriptional regulation of these oncogenic transcription factors, such as Nrf2 and HIF1α, leading to active transcription and expression of oncogenes and genes in the TGF and Nrf2 signaling pathways, which promotes carcinogenesis or tumorigenesis.
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Project description:Inorganic arsenic, a major environmental contaminant, has risen as an important health problem worldwide. More detailed identification of the molecular mechanisms associated with iAs exposure would help to establish better strategies for prevention and treatment. Although chronic iAs exposures have been previously studied there is little to no information regarding the early events of exposure to iAs. To better characterize the early mechanisms of iAs exposure we conducted gene expression studies using sublethal doses of iAs at two different time-points. The major transcripts differentially regulated at 2 hrs of iAs exposure included antioxidants, detoxificants and chaperones. Moreover, after 12 hrs of exposure many of the down-regulated genes were associated with DNA replication and S phase cell cycle progression. Interestingly, the most affected biological pathway by both 2 or 12 hrs of iAs exposure were the Nrf2-Keap1 pathway, represented by the highly up-regulated HMOX1 transcript, which is transcriptionally regulated by the transcription factor Nrf2. Additional Nrf2 targets included SQSTM1 and ABCB6, which were not previously associated with acute iAs exposure. Signalling pathways such as interferon, B cell receptor and AhR route were also responsive to acute iAs exposure. Since HMOX1 expression increased early (20 min) and was responsive to low iAs concentrations (0.1 M), this gene could be a suitable early biomarker for iAs exposure. In addition, the novel Nrf2 targets SQSTM1 and ABCB6 could play an important and previously unrecognized role in cellular protection against iAs
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Project description:Bacteria of the genus Thiomonas are found ubiquitously in arsenic contaminated waters such as Acid Mine Drainage (AMD), where they contribute to the precipitation and the natural bioremediation of arsenic. In these environments, these bacteria have developed a large range of resistance strategies, such as biofilm formation, which is one of the most ubiquitous adaptive response observed in prokaryotes to various stresses, such as those induced in the presence of toxic compounds. This study focused on the process of biofilm formation in several Thiomonas strains isolated from the same AMD. The results obtained here show that these bacteria are all capable of forming biofilms, but the architecture and the kinetics of formation of these biofilms differ depending on whether arsenic is present in the environment and from one strain to another. Indeed, two strains favored biofilm formation, whereas three others favored motility in the presence of arsenic. In order to identify the underlying mechanisms, the patterns of expression of some genes possibly involved in the process of biofilm formation were investigated in Thiomonas sp. CB2 in the presence and absence of arsenite, using a transciptomic approach (RNAseq). The findings obtained here shed interesting light on how the formation of biofilms and the motility processes contribute to the adaptation of Thiomonas strains to extreme environments.
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Project description:Inorganic arsenic, a major environmental contaminant, has risen as an important health problem worldwide. More detailed identification of the molecular mechanisms associated with iAs exposure would help to establish better strategies for prevention and treatment. Although chronic iAs exposures have been previously studied there is little to no information regarding the early events of exposure to iAs. To better characterize the early mechanisms of iAs exposure we conducted gene expression studies using sublethal doses of iAs at two different time-points. The major transcripts differentially regulated at 2 hrs of iAs exposure included antioxidants, detoxificants and chaperones. Moreover, after 12 hrs of exposure many of the down-regulated genes were associated with DNA replication and S phase cell cycle progression. Interestingly, the most affected biological pathway by both 2 or 12 hrs of iAs exposure were the Nrf2-Keap1 pathway, represented by the highly up-regulated HMOX1 transcript, which is transcriptionally regulated by the transcription factor Nrf2. Additional Nrf2 targets included SQSTM1 and ABCB6, which were not previously associated with acute iAs exposure. Signalling pathways such as interferon, B cell receptor and AhR route were also responsive to acute iAs exposure. Since HMOX1 expression increased early (20 min) and was responsive to low iAs concentrations (0.1 M-oM-^AM--M), this gene could be a suitable early biomarker for iAs exposure. In addition, the novel Nrf2 targets SQSTM1 and ABCB6 could play an important and previously unrecognized role in cellular protection against iAs We used human lymphoblastoid cell line (CL-1), immortalized with Epstein-Barr virus. Cell cultures were propagated in RPMI media supplemented with 10% fetal bovine serum (FBS), L-glutammine 2 mM and antiobiotics penicillin and 10 mg/ml streptomycin) at 37M-BM-:C in an atmosphere of 5% CO2. In the case of primary cultures, 1% phytohemaglutinine were added. Cell cultures (1x106) were treated with 5M-BM-5M sodium arsenite for 2 and 12 hrs while control cultures were incubated with PBS. Nine biological replicates for each condition were used for microarray analysis. After iAs treatment, total RNA from each biological replicate was isolated with Trizol. From the 9 biological replicates performed on each condition, we generated 3 pools at a concentration of 300 ng/M-BM-5L, where each pool was processed to a single microarray platform.
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