Nrf2 Drives Epigenetic Reprogramming and Acts as the Master Regulator of KLF4 Expression and Activity in Arsenic‐Induced Transformation

Abstract Emerging evidence suggests that Nrf2 plays a pro‐carcinogenic role in multiple cancers. Previous studies have shown that arsenic‐induced Nrf2 activation drives metabolic reprogramming, leading to the formation of cancer stem‐like cells. Here, we further demonstrate that KLF4, a key pluripotency factor, is a direct transcriptional target of Nrf2 in arsenic‐treated human bronchial epithelial cells (BEAS‐2B). Global chromatin immunoprecipitation sequencing (ChIP‐seq) revealed multiple Nrf2 binding peaks within the KLF4 locus, overlapping with the enhancer markers H3K4me1 and H3K27Ac. Nrf2 knockout diminished KLF4 expression and reduced enhancer marker enrichment, accompanied by a global decrease in KLF4 genomic occupancy in BEAS‐2B cells. Additionally, arsenic exposure enhances KLF4 binding at genes implicated in oncogenic pathways, including STAT3, SOX2, Nrf2 itself, cell growth regulators, Hedgehog signaling components, and epithelial‐to‐mesenchymal transition (EMT) markers. Notably, we identified a self‐reinforcing feedback loop between Nrf2 and KLF4 that amplifies their oncogenic effects. Finally, our data reveal that Nrf2‐KLF4 co‐occupancy is essential for establishing active enhancer hubs across the genome. Collectively, these findings suggest that Nrf2's oncogenic effects are, in part, mediated through the Nrf2‐dependent amplification of KLF4 expression and function. Targeting both Nrf2 and KLF4 may, therefore, represent a promising therapeutic strategy to eliminate arsenic‐induced cancer stem‐like cells.