Seno Akimasa, Bi Zhuoyue, Polin Lisa, Liu Ziqi, Qiu Yiran, Zhang Wenxuan, Pawar Aashna, Thakur Chitra, Seno Masaharu, Wang Ziwei, Chen Fei
Department of Biotechnology and Drug Discovery, Faculty of Interdisciplinary Science and Engineering in Health Systems, Institute of Academic & Research, Okayama University, Okayama 700-8530, Japan.
Stony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USA.
Redox Biol. 2025 Jul 17;86:103773. doi: 10.1016/j.redox.2025.103773.
Arsenic (As) is a well-established environmental carcinogen known to induce malignant transformation and cancer stem-like cell (CSC) properties in somatic cells, with Nrf2 functioning as a central regulator. However, the impact of chronic As exposure on pluripotent stem cells, particularly through Nrf2-mediated epigenetic and metabolic reprogramming, remains largely unexplored. In this study, we chronically exposed human induced pluripotent stem cells (iPSCs, Nips-B2) to an environmentally relevant concentration of trivalent arsenic (0.25 μM, As) for three months. The tumorigenic potential of exposed iPSCs was evaluated using anchorage-independent growth assays and xenograft models, while mechanistic insights were gained via chromatin immunoprecipitation sequencing (ChIP-seq) for Nrf2 and key histone modifications (H3K4me3, H3K9me3, H3K27me3, H3K36me3, and H4K20me3), alongside transcriptomic profiling by RNA sequencing (RNA-seq). Prolonged exposure markedly enhanced tumor sphere formation in vitro and accelerated tumor growth in vivo, indicating the acquisition of CSC-like traits. Integrated ChIP-seq and RNA-seq analyses revealed widespread Nrf2 chromatin binding and global epigenetic remodeling, characterized by increased levels of H3K27me3, H3K36me3, and H4K20me3, a modest rise in H3K9me3, and reduced H3K4me3. Notably, As exposure enhanced Nrf2 binding at loci regulating glycolysis, cholesterol biosynthesis, self-renewal, and oncogenesis. Functional analyses confirmed that transcriptional and metabolic changes were Nrf2-driven and closely linked to H3K36me3 and H3K27me3 dynamics. Collectively, our findings demonstrate that chronic As exposure reprograms iPSCs through Nrf2 activation and coordinated epigenetic remodeling, revealing a novel mechanism by which environmental carcinogens exploit stem cell plasticity to initiate CSC-like transformation.
砷（As）是一种公认的环境致癌物，已知可诱导体细胞发生恶性转化并具有癌症干细胞（CSC）样特性，其中Nrf2发挥着核心调节作用。然而，长期砷暴露对多能干细胞的影响，尤其是通过Nrf2介导的表观遗传和代谢重编程的影响，在很大程度上仍未得到探索。在本研究中，我们将人诱导多能干细胞（iPSCs，Nips-B2）长期暴露于环境相关浓度的三价砷（0.25 μM，As）中三个月。使用非锚定依赖性生长试验和异种移植模型评估暴露后的iPSCs的致瘤潜力，同时通过对Nrf2和关键组蛋白修饰（H3K4me3、H3K9me3、H3K27me3、H3K36me3和H4K20me3）进行染色质免疫沉淀测序（ChIP-seq）以及通过RNA测序（RNA-seq）进行转录组分析来深入了解其机制。长期暴露显著增强了体外肿瘤球的形成并加速了体内肿瘤的生长，表明获得了CSC样特征。综合ChIP-seq和RNA-seq分析揭示了广泛的Nrf2染色质结合和整体表观遗传重塑，其特征是H3K27me3、H3K36me3和H4K20me3水平升高，H3K9me3略有上升，H3K4me3降低。值得注意的是，砷暴露增强了Nrf2在调节糖酵解、胆固醇生物合成、自我更新和肿瘤发生的基因座上的结合。功能分析证实，转录和代谢变化是由Nrf2驱动的，并且与H3K36me3和H3K27me3动态密切相关。总的来说，我们的研究结果表明，长期砷暴露通过Nrf2激活和协调的表观遗传重塑对iPSCs进行重编程，揭示了一种环境致癌物利用干细胞可塑性引发CSC样转化 的新机制。
