LncRNA IDH1-AS1 links the functions of c-Myc and HIF1α via IDH1 to regulate the Warburg effect
Open accessAbstract
The oncoprotein c-Myc plays an important role in regulating glycolysis under normoxia; yet, in cancer cells, HIF1α, which is essential for driving glycolysis under hypoxia, is often up-regulated even in the presence of oxygen. The relationship between these two major regulators of the Warburg effect remains to be fully defined. Here we demonstrate that regulation of a long noncoding RNA (lncRNA), named IDH1-AS1, enables c-Myc to collaborate with HIF1α in activating the Warburg effect under normoxia. c-Myc transcriptionally repressed IDH1-AS1, which, upon expression, promoted homodimerization of IDH1 and thus enhanced its enzymatic activity. This resulted in increased α-KG and decreased ROS production and subsequent HIF1α down-regulation, leading to attenuation of glycolysis. Hence, c-Myc repression of IDH1-AS1 promotes activation of the Warburg effect by HIF1α. As such, IDH1-AS1 overexpression inhibited cell proliferation, whereas silencing of IDH1-AS1 promoted cell proliferation and cancer xenograft growth. Restoring IDH1-AS1 expression may therefore represent a potential metabolic approach for cancer treatment.
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The reviewed studies suggest involvement of Myc in the production of 2-HG.
“The above studies suggest the involvement of Myc in the production of 2-HG.”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [175]
The Results section reports that c-Myc regulates IDH1 activity, and the paper’s opening discussion of IDH metabolism states that specific IDH1 and IDH2 mutations convert α-KG into 2-HG (page numbers unavailable). These passages provide an indirect connection, but the paper does not show that Myc affects 2-HG production; it also reports in the Discussion that IDH1-AS1 does not bind the IDH1R132H mutant. (LLM, conf=0.81)
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Self-citation
- Authors
- Xiang, S., Gu, H., Jin, L., Thorne, R. F., Zhang, X. D., & Wu, M.
- Affiliations
- University of Science and Technology of China (CN)
- Henan University (CN)
- Corresponding author
- Zhang, Xu Dong
- Wu, Mian
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-01-29
- Volume
- 115
- Issue
- 7
- Pages
- E1465-E1474
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5816142
- OpenAlex
- W2793701251
- Cited by
- 129
- References
- 71
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 15 · 2023: 16 · 2022: 15 · 2021: 19 · 2020: 25 · 2019: 11 · 2018: 6
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81430065, 31371388)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- long non-coding RNA, c-Myc, HIF-1α, IDH1, Warburg effect, glycolysis, reactive oxygen species, hypoxia, cancer metabolism, cell proliferation
- MeSH terms
- Animals, Uterine Cervical Neoplasms, Female, Glycolysis, Humans, Isocitrate Dehydrogenase, Ketoglutaric Acids, Mice, Nude, Tumor Cells, Cultured, Transcriptional Activation, Proto-Oncogene Proteins c-myc, RNA, Antisense, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, RNA, Long Noncoding
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