Small Ubiquitin-related Modifier (SUMO)-1 Promotes Glycolysis in Hypoxia
Open accessAbstract
Under conditions of hypoxia, most eukaryotic cells undergo a shift in metabolic strategy, which involves increased flux through the glycolytic pathway. Although this is critical for bioenergetic homeostasis, the underlying mechanisms have remained incompletely understood. Here, we report that the induction of hypoxia-induced glycolysis is retained in cells when gene transcription or protein synthesis are inhibited suggesting the involvement of additional post-translational mechanisms. Post-translational protein modification by the small ubiquitin related modifier-1 (SUMO-1) is induced in hypoxia and mass spectrometric analysis using yeast cells expressing tap-tagged Smt3 (the yeast homolog of mammalian SUMO) revealed hypoxia-dependent modification of a number of key glycolytic enzymes. Overexpression of SUMO-1 in mammalian cancer cells resulted in increased hypoxia-induced glycolysis and resistance to hypoxia-dependent ATP depletion. Supporting this, non-transformed cells also demonstrated increased glucose uptake upon SUMO-1 overexpression. Conversely, cells overexpressing the de-SUMOylating enzyme SENP-2 failed to demonstrate hypoxia-induced glycolysis. SUMO-1 overexpressing cells demonstrated focal clustering of glycolytic enzymes in response to hypoxia leading us to hypothesize a role for SUMOylation in promoting spatial re-organization of the glycolytic pathway. In summary, we hypothesize that SUMO modification of key metabolic enzymes plays an important role in shifting cellular metabolic strategies toward increased flux through the glycolytic pathway during periods of hypoxic stress.
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Overexpression of SUMO-1 in cancer cells increases hypoxia-induced glycolysis and resistance to hypoxia-dependent ATP depletion.
“Overexpression of SUMO-1 in cancer cells resulted in increased hypoxia-induced glycolysis and resistance to hypoxia-dependent ATP depletion [98].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [98]
Hypoxia-induced glycolysis is retained when gene transcription or protein synthesis is inhibited, suggesting involvement of post-translational mechanisms.
“In the context of cellular metabolism, Agbor et al. first observed that the induction of hypoxia-induced glycolysis was retained by cells when gene transcription or protein synthesis were inhibited, suggesting the involvement of additional post-translational mechanisms [98].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [98]
Novel HIF-1-independent mechanisms regulating glycolysis under hypoxia include epigenetic reprogramming, post-translation modifications, spatial reorganization of glycolytic enzymes, and PI3K-Akt-mTOR signalling.
“Insights into novel HIF-1-independent mechanisms regulating glycolysis under hypoxia that emerged in the last decade include epigenetic reprogramming [97], post-translation modifications [98], spatial reorganization of glycolytic enzymes [98,99] and the PI3K-Akt-mTOR signalling pathway [100].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [98]
SUMOylation may promote spatial reorganisation of the glycolytic pathway, as indicated by focal clustering of glycolytic enzymes in response to hypoxia.
“Intriguingly, these cells also demonstrated focal clustering of glycolytic enzymes in response to hypoxia, suggesting that SUMOylation may promote spatial reorganisation of the glycolytic pathway [98], another mechanism by which glycolysis can be regulated that is discussed below.”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [98]
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Cites
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Mitochondria and cellular oxygen sensing in the HIF pathway
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Self-citationSumoylation increases HIF-1α stability and its transcriptional activity
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Flagged first, then by citations
Research works printed but not linked: 3
- Comerford, K. M., Leonard, M. O., Karhausen, J., Carey, R., Colgan, S. P., and Taylor, C. T. (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 986 -991
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Cited by
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Regulation of glycolysis by the hypoxia-inducible factor (HIF): Implications for cellular physiology
Kierans, S. J., & Taylor, C. T. (2021) · The Journal of Physiology · doi:10.1113/jp280572 · Cited by 1,015 · see citing works
Self-citationHIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells
Lee, S.-H., Golinska, M., & Griffiths, J. R. (2021) · Cells · doi:10.3390/cells10092371 · Cited by 169 · see citing works
- Authors
- Agbor, T. A., Cheong, A., Comerford, K. M., Scholz, C. C., Bruning, U., Clarke, A., Cummins, E. P., Cagney, G., & Taylor, C. T.
- Affiliations
- University College Dublin (IE)
- Corresponding author
- Taylor, Cormac T.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-02
- Volume
- 286
- Issue
- 6
- Pages
- 4718-4726
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3039330
- OpenAlex
- W2036084208
- Cited by
- 68
- References
- 6
- Citations by year
- 2025: 4 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 7 · 2019: 5 · 2018: 5 · 2017: 3 · 2016: 6 · 2015: 3 · 2014: 3 · 2013: 9
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Aston Publications Explorer (Aston University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- SUMO1, hypoxia, glycolysis, SUMOylation, post-translational modification, glycolytic enzymes, deSUMOylation, glucose uptake, metabolic reprogramming, cancer cells, ATP depletion, Smt3
- MeSH terms
- Adenosine Triphosphate, Cysteine Endopeptidases, Glycolysis, HeLa Cells, Humans, Protein Processing, Post-Translational, Cell Hypoxia, Small Ubiquitin-Related Modifier Proteins, SUMO-1 Protein
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