Nrf2 orchestrates epigenetic regulations and serves as the master regulator of KLF4 expression and activity during arsenic-induced transformation
Wang, Z.; Bi, Z.; Bamrah, J.; Qiu, Y.; Zhang, W.; Ji, H.; Haley, J.; Thakur, C.; Chen, F.
Show abstract
Emerging evidence suggests that Nrf2 plays a pro-carcinogenic role in cancer. Our previous study showed that arsenic-induced Nrf2 activation triggers metabolic reprogramming, leading to the formation of cancer stem-like cells. Here, we further demonstrated that KLF4, a key pluripotency factor, is a direct transcriptional target of Nrf2 in arsenic-exposed human bronchial epithelial cells. ChIP-seq analysis identified multiple Nrf2 binding peaks at the Klf4 gene locus, which overlap with the enhancer markers H3K4me1 and H3K27Ac. Nrf2 knockout reduced both KLF4 expression and enhancer marker enrichment, accompanied by a global decrease in KLF4 binding across the genome. In wild-type (WT) cells, arsenic treatment increased KLF4 binding on genes involved in oncogenic pathways such as STAT3, SOX2, Nrf2, cell growth, Hedgehog, and EMT. We also found that KLF4 engages in a self-feedback loop in response to Nrf2 signaling. Lastly, our data showed that the co-occupancy of Nrf2 and KLF4 is crucial for establishing active enhancer hubs in the genome. These findings suggest that Nrf2s oncogenic effects are, in part, mediated by Nrf2 dependent self-amplification of KLF4 expression and function. Thus, targeting both Nrf2 and KLF4 could be a promising therapeutic strategy for eliminating cancer stem-like cells.
Matching journals
The top 12 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- NRF1 and NRF3 complementarily maintain a basal proteasome activity in cancer cells through CPEB3-mediated translational repression 92%
- A novel cis regulatory element regulates human XIST in CTCF-dependent manner 92%
- Histone chaperone Nucleophosmin regulates transcription of key genes involved in oral tumorigenesis. 92%
Similar papers in this journal
- Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer 93%
- Sequential deregulation of histone marks, chromatin accessibility and gene expression in response to PROTAC-induced degradation of ASH2L 92%
- Arsenic hexoxide has differential effects on cell proliferation and genome-wide gene expression in human primary mammary epithelial and MCF7 cells 92%
Similar papers in this journal
- S100a4+ alveolar macrophages accelerate the progression of precancerous atypical adenomatous hyperplasia by promoting the angiogenic function regulated by fatty acid metabolism 93%
- Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer 93%
- Super-Enhancer Driven ZFP36L1 Promotes PD-L1 Expression in Infiltrative Gastric Cancer 93%
Similar papers in this journal
- Manipulating PARK7/DJ-1 Levels by Genotoxic Stress Alters Noncoding RNAs and Cellular Homeostasis 93%
- Impaired p53-mediated DNA damage response contributes to microcephaly in Nijmegen Breakage Syndrome patient-derived cerebral organoids 92%
- Differential occupancy and regulatory interactions of KDM6A in bladder cell lines 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.