ArticleMolecular cancer2025
RHOA lactylation at oncogenic hotspots promotes oncogenic activity and protein stabilization.
Article in Molecular cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- CD112 Lactylation Drives Dual Immune Evasion From CD8+ T Cells and NK Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Lactate metabolism and protein lactylation in programmed cell death: From novel mechanism to therapeutic strategies in human diseases.Clinical and translational medicine · 2026Review
- ACAT1-Mediated SP1-K694 Lactylation Promotes M1 Macrophage Polarization via TREM1 Transcription in COPD.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Histone deacetylases in cancer metabolic reprogramming.Experimental & molecular medicine · 2026Review
- The crosstalk between RNA m6A modification and protein lactylation: emerging insights into tumor progression.Oncogene · 2026Review
- Crosstalk between lactylation and other post-translational modifications in health and diseases.Molecular biomedicine · 2026Review
- Non-canonical and constitutive activation of small GTPases: more than an exception to the rule?The Biochemical journal · 2026Review
- HDAC3 as an Immunometabolic Rheostat: Molecular Mechanisms of Deacylation Plasticity, Lactylation Dynamics, and Spatiotemporal Regulation.Biomolecules · 2026Review
- Protein lactylation in Alzheimer's disease: bridging metabolism, pathology, and therapeutic opportunity.Frontiers in aging neuroscience · 2026Review
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7 authors.
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Abstract
backgroundAberrant RHOA activation drives tumor progression, yet regulatory mechanisms beyond genetic mutations remain poorly defined. Lactylation, a lactate-derived post-translational modification, links metabolic reprogramming to oncogenesis, but its functional mimicry of genetic mutations is unexplored. This study investigates RHOA lactylation at oncogenic hotspots and its role as an "epi-mutation" system.
methodsRHOA lactylation were identified by pan-lysine lactylation (Kla) antibody-based mass spectrometry. Site-specific lactylation was achieved using an orthogonal Mb-Pyl Kla-RS/Pyl-tRNA pair to incorporate lactyl-lysine at K118/K162 in recombinant RHOA, validated by immunoblotting and fluorescence. Molecular dynamics simulations (AlphaFold 3, BIOVIA DS) analyzed GTPase activity and hydrogen-bond networks. RHOA activity was assessed via ROCK2-RBD pull-down and GTPase assays. Ubiquitination and protein stability were examined using cycloheximide chase and K48/K63-ubiquitin mutants. In vitro lactylation/delactylation assays with PCAF/HDAC3 defined enzyme specificity. In vitro/in vivo functional studies used migration/invasion assays and xenograft models. Clinical relevance was evaluated in breast cancer tissues and survival databases.
resultsWe identify lactylation of RHOA at oncogenic mutation hotspots K118 and K162, mediated by the lactate-PCAF/HDAC3 axis. Mechanistically, K118 lactylation constitutively activates RHOA by impairing intrinsic GTPase activity, whereas K162 lactylation stabilizes RHOA protein by competitively antagonizing protein ubiquitination, with USP9X further enhancing stability through deubiquitination. Functionally, RHOA lactylation promotes tumor cell migration, invasion and metastasis. Clinically, RHOA lactylation is elevated in breast tumors versus adjacent tissues. Notably, targeting lactate production (LDHA inhibitor: sodium oxamate) synergized with RHOA-pathway inhibition (ROCK inhibitor: Y-27632) to suppress tumor progression. By employing a site-specific lactylation system, we further identify that lactylation mimics oncogenic mutations by enhancing both RHOA activity and stability, thus proposing that lactylation at mutation-prone sites represents a reversible "epi-mutation" system that recapitulates genetic mutation effects.
conclusionsRHOA lactylation at K118 (activation) and K162 (stabilization) orchestrated by the PCAF/HDAC3 enzymatic axis, enables constitutive oncogenic signaling to fuel tumor progression. Crucially, we redefine that lactylation at mutation-prone sites functions as a reversible "epi-mutation" system, where metabolic modification dynamically recapitulates oncogenic mutation effects, challenging the genetic/epigenetic dichotomy in oncology and revealing dual targeting of lactylation and canonical RHOA pathways as a potential therapeutic strategy.
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