Enhancer-bound Nrf2 Licenses HIF-1α Transcription under Hypoxia to Promote Cisplatin Resistance in Hepatocellular Carcinoma Cells
Open accessAbstract
Tumor microenvironment is hypoxic, which can cause resistance to chemotherapy, but the detailed mechanisms remain elusive. Here we find that mild hypoxia (5% O(2)) further increases cisplatin resistance in the already resistant HepG2/DDP but not the sensitive HepG2 cells. We find that Nrf2 is responsible for cisplatin resistance under hypoxia, as Nrf2 knockdown sensitizes HepG2/DDP cells while Nrf2 hyper-activation (though KEAP1 knockdown) increases resistance of HepG2 cells to cisplatin. Nrf2 binds to an enhancer element in the upstream of HIF-1α gene independently of hypoxia, promoting HIF-1α mRNA synthesis under hypoxic condition. As a result, Nrf2-dependent transcription counteracts HIF-1α degradation under mild hypoxia condition, leading to preferential cisplatin-resistance in HepG2/DDP cells. Our data suggest that Nrf2 regulation of HIF-1α could be an important mechanism for chemotherapy resistance in vivo.
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In hypoxia, NRF2 activates HIF1α and an array of multidrug resistance genes (MDR1/ABCB1, MRP1/ABCC1, BCRP/ABCG2) resulting in resistance to a variety of other chemotherapeutics.
“On the other hand, in hypoxia oxygenic stress response is activated by NRF2, which activates HIF1α, but more importantly an array of multidrug resistance genes such as MDR1/ABCB1, MRP1/ABCC1 and BCRP/ABCG2 resulting in resistance to a variety of other chemotherapeutics [59, 60].”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [59]
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- Authors
- Jin, X., Gong, L., Peng, Y., Li, L., & Liu, G.
- Affiliations
- Central South University (CN)
- Hunan Yuantai Biotechnology Co., Ltd, Changsha 410000, Hunan, China
- Corresponding author
- Liu, Gang
- Venue
- Aging
- Publisher
- Impact Journals, LLC
- Published
- 2020-12-03
- Volume
- 13
- Issue
- 1
- Pages
- 364-375
- ISSN
- 1945-4589 (ISSN-L)
- PMC
- PMC7835028
- OpenAlex
- W3107962586
- Cited by
- 24
- References
- 55
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 3
- FWCI
- 0.97
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- cc-by
- Locations
- Aging (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- Nrf2, HIF-1α, enhancer binding, hypoxia, cisplatin resistance, hepatocellular carcinoma, transcriptional regulation, chemoresistance
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Tumor Hypoxia, Antineoplastic Agents, Cisplatin, Enhancer Elements, Genetic, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, NF-E2-Related Factor 2, Hypoxia-Inducible Factor 1, alpha Subunit, Gene Knockdown Techniques, Hep G2 Cells, Tumor Microenvironment
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