Ketogenesis promotes triple-negative breast cancer metastasis via calpastatin β-hydroxybutyrylation

• Published in: Lipids in health and disease 2024-11, Vol.23 (1), p.371-11, Article 371
• Main Authors: Jiang, Haoran, Zeng, Yuan, Yuan, Xiaoye, Chen, Liwen, Xu, Xuni, Jiang, Xue, Li, Quan, Li, Gang, Yang, Han
• Format: Article
• Language: English
• Subjects: 3-Hydroxybutyric Acid - metabolism; Animals; Breast cancer; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Calpain - genetics; Calpain - metabolism; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Female; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - metabolism; Gene Expression Regulation, Neoplastic; Humans; Ketogenesis; Metastasis; Mice; Neoplasm Metastasis; Phosphorylation; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; β-hydroxybutyrylation
• ISSN: 1476-511X; 1476-511X
• DOI: 10.1186/s12944-024-02364-x

Triple-negative breast cancer (TNBC) continues to pose a significant obstacle in the field of oncology. Dysregulation of lipid metabolism, notably upregulated ketogenesis, has emerged as a hallmark of TNBC, yet its role in metastasis has been elusive. Here, by utilizing clinical specimens and experimental models, the study demonstrates that increased ketogenesis fosters TNBC metastasis by promoting the up-regulation of β-hydroxybutyrate (β-OHB), a key ketone body. Mechanistically, β-OHB facilitates β-hydroxybutyrylation (Kbhb) of Calpastatin (CAST), an endogenous calpain (CAPN) inhibitor, at K43, blocking the interaction with CAPN and subsequently promoting FAK phosphorylation and epithelial‒mesenchymal transition (EMT). In conclusion, the study reveals a novel regulatory axis linking ketogenesis to TNBC metastasis, shedding light on the intricate interplay between metabolic reprogramming and tumor progression.