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β-Hydroxybutyrate promotes cancer metastasis through β-hydroxybutyrylation-dependent stabilization of Snail

Author

Listed:
  • Wenna Jiang

    (Tianjin’s Clinical Research Center for Cancer)

  • Meng Wang

    (Tianjin’s Clinical Research Center for Cancer
    The Second Hospital of Tianjin Medical University)

  • Jiayi Wang

    (Tianjin’s Clinical Research Center for Cancer)

  • Qianhui Hao

    (Tianjin’s Clinical Research Center for Cancer)

  • Yuxuan Li

    (Tianjin’s Clinical Research Center for Cancer)

  • Lin Liu

    (Tianjin’s Clinical Research Center for Cancer)

  • Tianxing Zhou

    (Tianjin’s Clinical Research Center for Cancer)

  • Wei Song

    (Nanjing Agricultural University)

  • Jing Liu

    (Shanghai Cancer Center
    Fudan University)

  • Miao Liu

    (Tianjin’s Clinical Research Center for Cancer)

  • Yongjie Xie

    (Tianjin’s Clinical Research Center for Cancer)

  • Duo Zuo

    (Tianjin’s Clinical Research Center for Cancer)

  • Jiawei Xiao

    (Tianjin’s Clinical Research Center for Cancer)

  • Xiuse Zhang

    (Tianjin’s Clinical Research Center for Cancer)

  • Shan Gao

    (Southeast University)

  • Li Ren

    (Tianjin’s Clinical Research Center for Cancer)

  • Jihui Hao

    (Tianjin’s Clinical Research Center for Cancer)

Abstract

β-Hydroxybutyrylation (Kbhb) modification regulates protein molecular fates in either physiology or pathology, including cancer. However, the function and regulatory mechanism of Kbhb remain completely unknown in cancer metastasis. Here, we report that β-hydroxybutyrate (BHB) is clinically associated with the progression of pancreatic cancer and functionally promotes pancreatic cancer cell metastasis. Mechanistically, BHB induces Kbhb modification of Snail at lysine 152 to enhance Snail stabilization, which is regulated by Kbhb modification enzyme CREB-binding protein (CBP), and subsequently prevents Snail degradation by blocking recognition of E3 ubiquitin ligases FBXL14. Furthermore, either targeting Snail Kbhb modification or CBP inhibitor decreases cancer metastasis and enhances the therapeutic efficacy of gemcitabine in pancreatic cancer cells. Collectively, our study reveals that Kbhb of Snail is critical to promote metastasis and provides a potential therapeutic strategy.

Suggested Citation

  • Wenna Jiang & Meng Wang & Jiayi Wang & Qianhui Hao & Yuxuan Li & Lin Liu & Tianxing Zhou & Wei Song & Jing Liu & Miao Liu & Yongjie Xie & Duo Zuo & Jiawei Xiao & Xiuse Zhang & Shan Gao & Li Ren & Jihu, 2025. "β-Hydroxybutyrate promotes cancer metastasis through β-hydroxybutyrylation-dependent stabilization of Snail," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61541-3
    DOI: 10.1038/s41467-025-61541-3
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