Wang Ziwei, Bi Zhuoyue, Bamrah Jessica, Qiu Yiran, Zhang Wenxuan, Almutairy Bandar Saeed, Ji Haoyan, Haley John D, Thakur Chitra, Chen Fei
Stony Brook Cancer Center and Department of Pathology, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, 11961, Saudi Arabia.
Adv Sci (Weinh). 2025 Aug 4:e00221. doi: 10.1002/advs.202500221.
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.
新出现的证据表明，Nrf2在多种癌症中发挥促癌作用。先前的研究表明，砷诱导的Nrf2激活驱动代谢重编程，导致癌症干细胞样细胞的形成。在此，我们进一步证明，关键的多能性因子KLF4是砷处理的人支气管上皮细胞（BEAS-2B）中Nrf2的直接转录靶点。全基因组染色质免疫沉淀测序（ChIP-seq）揭示了KLF4基因座内多个Nrf2结合峰，与增强子标记H3K4me1和H3K27Ac重叠。Nrf2基因敲除降低了KLF4的表达并减少了增强子标记富集，同时BEAS-2B细胞中KLF4基因组占有率整体下降。此外，砷暴露增强了KLF4在与致癌途径相关基因上的结合，这些基因包括STAT3、SOX2、Nrf2自身、细胞生长调节因子、Hedgehog信号成分和上皮-间质转化（EMT）标记物。值得注意的是，我们发现了Nrf2和KLF4之间的自我强化反馈环，放大了它们的致癌作用。最后，我们的数据表明，Nrf2-KLF4共占据对于在全基因组中建立活跃的增强子枢纽至关重要。总体而言，这些发现表明，Nrf2的致癌作用部分是通过Nrf2依赖性的KLF4表达和功能放大介导的。因此，靶向Nrf2和KLF4可能是消除砷诱导的癌症干细胞样细胞的一种有前景的治疗策略。
