Aerobic glycolysis tunes YAP/TAZ transcriptional activity
Open accessAbstract
Increased glucose metabolism and reprogramming toward aerobic glycolysis are a hallmark of cancer cells, meeting their metabolic needs for sustained cell proliferation. Metabolic reprogramming is usually considered as a downstream consequence of tumor development and oncogene activation; growing evidence indicates, however, that metabolism on its turn can support oncogenic signaling to foster tumor malignancy. Here, we explored how glucose metabolism regulates gene transcription and found an unexpected link with YAP/TAZ, key transcription factors regulating organ growth, tumor cell proliferation and aggressiveness. When cells actively incorporate glucose and route it through glycolysis, YAP/TAZ are fully active; when glucose metabolism is blocked, or glycolysis is reduced, YAP/TAZ transcriptional activity is decreased. Accordingly, glycolysis is required to sustain YAP/TAZ pro-tumorigenic functions, and YAP/TAZ are required for the full deployment of glucose growth-promoting activity. Mechanistically we found that phosphofructokinase (PFK1), the enzyme regulating the first committed step of glycolysis, binds the YAP/TAZ transcriptional cofactors TEADs and promotes their functional and biochemical cooperation with YAP/TAZ. Strikingly, this regulation is conserved in Drosophila, where phosphofructokinase is required for tissue overgrowth promoted by Yki, the fly homologue of YAP. Moreover, gene expression regulated by glucose metabolism in breast cancer cells is strongly associated in a large dataset of primary human mammary tumors with YAP/TAZ activation and with the progression toward more advanced and malignant stages. These findings suggest that aerobic glycolysis endows cancer cells with particular metabolic properties and at the same time sustains transcription factors with potent pro-tumorigenic activities such as YAP/TAZ.
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PFK1 directly binds to and regulates YAP and TAZ.
“In another study, the Dupont group showed that the glycolytic enzyme phosphofructokinase ( PFK1 ) directly binds to and regulates YAP and TAZ (36).”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [36]
The paper reports that PFK1 knockdown inhibited YAP/TAZ activity, supporting the regulation part of the claim. But in its discussion of YAP interaction (page not supplied), the authors say they could hardly detect direct PFK1–YAP binding; they instead found that PFK1 binds TEAD proteins. The claimed direct binding to YAP and TAZ is therefore not supported. (LLM, conf=0.90)
Experimental — accuracy not yet measuredBoth glucose starvation and AMPK activators inhibit Yap in different cell types.
“Both glucose starvation (36, 100, 145) and AMPK activators (26, 100, 145) inhibit Yap in different cell types.”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [36]
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USP15 is a deubiquitylating enzyme for receptor-activated SMADs
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Prolyl‐isomerase Pin1 controls normal and cancer stem cells of the breast
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Targeting Unique Metabolic Properties of Breast Tumor Initiating Cells
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Flagged first, then by citations
Research works printed but not linked: 2
- Elena Enzo et al Glycolysis tunes YAP/TAZ activity The EMBO Journal
- Yang Y, Lane AN, Ricketts CJ, Sourbier C, Wei M-H, Shuch B, Pike L, Wu M, Rouault TA, Boros LG, Fan TWM, Linehan WM (2013) Metabolic ª 2015 The Authors The EMBO Journal Vol 34 | No 10 | 2015
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GAM: a web-service for integrated transcriptional and metabolic network analysis
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- Authors
- Enzo, E., Santinon, G., Pocaterra, A., Aragona, M., Bresolin, S., Forcato, M., Grifoni, D., Pession, A., Zanconato, F., Guzzo, G., Bicciato, S., & Dupont, S.
- Affiliations
- University of Padua (IT)
- University of Modena and Reggio Emilia (IT)
- University of Bologna (IT)
- Corresponding author
- Dupont, Sirio
- ORCID
- Venue
- The EMBO Journal
- Published
- 2015-03-21
- Volume
- 34
- Issue
- 10
- Pages
- 1349-1370
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC4491996
- OpenAlex
- W2168636113
- Cited by
- 414
- References
- 112
- Citations by year
- 2026: 23 · 2025: 41 · 2024: 49 · 2023: 39 · 2022: 54 · 2021: 46 · 2020: 41 · 2019: 42 · 2018: 42 · 2017: 11 · 2016: 17 · 2015: 8
- FWCI
- 13.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Archivio Istituzionale della Ricerca - Università degli Studi dell Aquila (submittedVersion, public-domain)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Funders
- AIRC (IG15307)
- MIUR/PRIN
- PRAT University of Padova
- FIRB Accordi di Programma 2011 (RBAP11T3WB)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- aerobic glycolysis, YAP/TAZ, TEAD transcription factors, phosphofructokinase-1, glucose metabolism, tumor metabolic reprogramming, transcriptional regulation, breast cancer, Yki, tumor progression, oncogenic signaling
- MeSH terms
- YAP-Signaling Proteins, Acyltransferases, Animals, Bacteria, Aerobic, Drosophila, Glycolysis, Humans, Phosphoproteins, Transcription Factors, Cell Line, Tumor, Chromatin Immunoprecipitation, Immunoprecipitation, Adaptor Proteins, Signal Transducing, Real-Time Polymerase Chain Reaction
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