{"doi":"10.7150/thno.42903","title":"Nrf2 and HIF1α converge to arsenic-induced metabolic reprogramming and the formation of the cancer stem-like cells","abstract":"In this report, we demonstrated that inorganic arsenic (iAs) induces generation of the cancer stem-like cells (CSCs) through Nrf2-dependent HIF1 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 HIF1 on the genome in the cells treated with iAs. Both untargeted metabolomics and UDP-13 C-glucose flux were applied to determine metabolic reprogramming in the iAs-induced CSCs. The role of Nrf2 on iAs-induced HIF1 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 HIF1 peaks from distal intergenic region to gene promoter and the first exon was noted. Both Nrf2 and HIF1 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 HIF1. Inhibition of Nrf2 by lentiviral infection of Keap1, or knockout of Nrf2 by CRISPR-Cas9 gene editing, not only blocked iAs-induced HIF1 activation, but reduced the expression of the key stemness genes for the formation of CSCs also.","journal":"Theranostics","year":2020,"id":65246,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":60,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9631,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":345059,"name":"Qian Zhang","orcid":"0009-0001-6172-4411","position":1,"is_corresponding":false},{"id":62035,"name":"Yao Fu","orcid":"0000-0001-9864-1030","position":2,"is_corresponding":false},{"id":346484,"name":"Priya Wadgaonkar","orcid":null,"position":3,"is_corresponding":false},{"id":73951,"name":"Wenxuan Zhang","orcid":"0000-0002-2046-3366","position":4,"is_corresponding":false},{"id":73956,"name":"Bandar Almutairy","orcid":null,"position":5,"is_corresponding":false},{"id":345060,"name":"Liping Xu","orcid":"0000-0003-3370-2386","position":6,"is_corresponding":false},{"id":346485,"name":"M’Kya Rice","orcid":null,"position":7,"is_corresponding":false},{"id":73950,"name":"Yiran Qiu","orcid":"0000-0001-8669-1209","position":8,"is_corresponding":false},{"id":73955,"name":"Chitra Thakur","orcid":"0000-0002-4356-2543","position":9,"is_corresponding":false},{"id":345061,"name":"Fei Chen","orcid":"0000-0002-7600-1945","position":10,"is_corresponding":false},{"id":73948,"name":"Zhuoyue Bi","orcid":"0000-0001-8559-3543","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-18T21:13:23.327603Z","pmid":"32226544","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}