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PreprintCited by 26Cancer, Hypoxia, and MetabolismMelanoma and MAPK PathwaysProtein Kinase Regulation and GTPase Signaling

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Lactate accelerates cancer progression through the ERK-GCN5 lactylation-phosphorylation feedback cascade

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Yuan, Jian, Huang, Bingsong, Chen, Yuping, Cui, Gaofeng, Mer, Georges, Zhong, Chunlong·2024·Nature Chemical Biology
DOI 10.21203/rs.3.rs-3944681/v1

Preprint — published as 10.1038/s41589-025-02107-8 · Paper page

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Abstract

The Warburg effect released lactate promotes cancer progression, but the mechanisms remain unclear. Here, we found lactate activated MAPK pathway through ERK-lactylation to promote cancer progression. Moreover, we identified the GCN5 as the lactyl-transferase for ERK lactylation. Interestingly, activated ERK phosphorylated GCN5 and promoted GCN5 lactyl-transferase activity for ERK, which formed the positive feedback loop to facilitate lactate-mediated cancer progression. Mechanistically, ERK-K231 lactylation decreased the dissociation energy between ERK and MEK, due to the reduced electrostatic interaction between ERK-K231 and MEK-D217. This facilitated the dissociation of ERK from MEK kinases, which in turn induced ERK dimerization and activation. Hence, we developed a cell-penetrating peptide to specifically inhibit the ERK lactylation, and demonstrated the peptide impaired the tumor growth with KRAS-mutant. Taken together, we define a molecular mechanism that lactate accelerates cancer progression through ERK-GCN5 lactylation-phosphorylation cascade and provide a strategy to target ERK lactylation, especially for RAS-MAPK-driven cancers.

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Metadata

Authors
Yuan, J., Huang, B., Chen, Y., Cui, G., Mer, G., & Zhong, C.
Affiliations
  • Tongji University (CN)
  • Mayo Clinic (US)
Corresponding author
  • Yuan, Jian
  • Chen, Yuping
  • Zhong, Chunlong
ORCID
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2024-02-22
Volume
22
Issue
4
Pages
634-648
ISSN
1552-4450 (ISSN-L)
DOI
10.21203/rs.3.rs-3944681/v1
OpenAlex
W7123363086
Cited by
26
References
1
Citations by year
2026: 26
FWCI
81.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Chemical Biology (publishedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (81571184, 81771332, 82172820, 82271406)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
GCN5, lactate, Warburg effect, MAPK signaling, ERK1/2 phosphorylation, positive feedback loop, cell-penetrating peptides, KRAS-mutant cancer, tumor growth
MeSH terms
Animals, Humans, Neoplasms, Phosphorylation, Disease Progression, Lactic Acid, MAP Kinase Signaling System, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Mice

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