Theranostics 2020; 10(9):4134-4149. doi:10.7150/thno.42903 This issue Cite

Research Paper

Nrf2 and HIF1α converge to arsenic-induced metabolic reprogramming and the formation of the cancer stem-like cells

Zhuoyue Bi1,2,3, Qian Zhang1, Yao Fu1, Priya Wadgaonkar1, Wenxuan Zhang1, Bandar Almutairy1,4, Liping Xu1, M'Kya Rice1, Yiran Qiu1, Chitra Thakur1, Fei Chen1✉

1. Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
2. School of Health Sciences, Wuhan University, 115 Donghu Road, Wuhan 430071, China
3. Hubei Provincial Key Laboratory of Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, 8 Zhudaoquanbei Road, Wuhan 430079, China
4. College of Pharmacy, Al-Dawadmi Campus, Shaqra University, P.O.Box 11961, Riyadh, Kingdom of Saudi Arabia.

Citation:
Bi Z, Zhang Q, Fu Y, Wadgaonkar P, Zhang W, Almutairy B, Xu L, Rice M, Qiu Y, Thakur C, Chen F. Nrf2 and HIF1α converge to arsenic-induced metabolic reprogramming and the formation of the cancer stem-like cells. Theranostics 2020; 10(9):4134-4149. doi:10.7150/thno.42903. https://www.thno.org/v10p4134.htm
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Abstract

Graphic abstract

In this report, we demonstrated that inorganic arsenic (iAs) induces generation of the cancer stem-like cells (CSCs) through Nrf2-dependent HIF1α 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 HIF1α on the genome in the cells treated with iAs. Both untargeted metabolomics and UDP-13C-glucose flux were applied to determine metabolic reprogramming in the iAs-induced CSCs. The role of Nrf2 on iAs-induced HIF1α 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 HIF1α peaks from distal intergenic region to gene promoter and the first exon was noted. Both Nrf2 and HIF1α 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 HIF1α. Inhibition of Nrf2 by lentiviral infection of Keap1, or knockout of Nrf2 by CRISPR-Cas9 gene editing, not only blocked iAs-induced HIF1α activation, but reduced the expression of the key stemness genes for the formation of CSCs also.

Conclusion: We demonstrated that Nrf2 activation is an initiating signal for iAs-induced HIF1α activation, and Nrf2 and HIF1α played a concerted role on inducing metabolic reprogramming and the CSCs.

Keywords: arsenic, Nrf2, HIF1α, metabolic reprogramming, cancer stem cells


Citation styles

APA
Bi, Z., Zhang, Q., Fu, Y., Wadgaonkar, P., Zhang, W., Almutairy, B., Xu, L., Rice, M., Qiu, Y., Thakur, C., Chen, F. (2020). Nrf2 and HIF1α converge to arsenic-induced metabolic reprogramming and the formation of the cancer stem-like cells. Theranostics, 10(9), 4134-4149. https://doi.org/10.7150/thno.42903.

ACS
Bi, Z.; Zhang, Q.; Fu, Y.; Wadgaonkar, P.; Zhang, W.; Almutairy, B.; Xu, L.; Rice, M.; Qiu, Y.; Thakur, C.; Chen, F. Nrf2 and HIF1α converge to arsenic-induced metabolic reprogramming and the formation of the cancer stem-like cells. Theranostics 2020, 10 (9), 4134-4149. DOI: 10.7150/thno.42903.

NLM
Bi Z, Zhang Q, Fu Y, Wadgaonkar P, Zhang W, Almutairy B, Xu L, Rice M, Qiu Y, Thakur C, Chen F. Nrf2 and HIF1α converge to arsenic-induced metabolic reprogramming and the formation of the cancer stem-like cells. Theranostics 2020; 10(9):4134-4149. doi:10.7150/thno.42903. https://www.thno.org/v10p4134.htm

CSE
Bi Z, Zhang Q, Fu Y, Wadgaonkar P, Zhang W, Almutairy B, Xu L, Rice M, Qiu Y, Thakur C, Chen F. 2020. Nrf2 and HIF1α converge to arsenic-induced metabolic reprogramming and the formation of the cancer stem-like cells. Theranostics. 10(9):4134-4149.

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