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AMPK induces degradation of the transcriptional repressor PROX1 impairing branched amino acid metabolism and tumourigenesis

Author

Listed:
  • Yanan Wang

    (Shanghai Jiao Tong University)

  • Mengjun Luo

    (Fudan University)

  • Fan Wang

    (Shanghai Jiao Tong University)

  • Yu Tong

    (Shanghai Jiao Tong University)

  • Linfeng Li

    (Shanghai Jiao Tong University)

  • Yu Shu

    (Shanghai Jiao Tong University)

  • Ke Qiao

    (Fudan University)

  • Lei Zhang

    (Fudan University)

  • Guoquan Yan

    (Fudan University)

  • Jing Liu

    (Fudan University)

  • Hongbin Ji

    (University of Chinese Academy of Sciences)

  • Youhua Xie

    (Fudan University
    Fudan University)

  • Yonglong Zhang

    (Shanghai Jiao Tong University Affiliated Sixth People’s Hospital)

  • Wei-Qiang Gao

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Yanfeng Liu

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

Abstract

Tumour cell metabolic plasticity is essential for tumour progression and therapeutic responses, yet the underlying mechanisms remain poorly understood. Here, we identify Prospero-related homeobox 1 (PROX1) as a crucial factor for tumour metabolic plasticity. Notably, PROX1 is reduced by glucose starvation or AMP-activated protein kinase (AMPK) activation and is elevated in liver kinase B1 (LKB1)-deficient tumours. Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. Downregulation of PROX1 activates branched-chain amino acids (BCAA) degradation through mediating epigenetic modifications and inhibits mammalian target-of-rapamycin (mTOR) signalling. Importantly, PROX1 deficiency or Ser79 phosphorylation in liver tumour shows therapeutic resistance to metformin. Clinically, the AMPK-PROX1 axis in human cancers is important for patient clinical outcomes. Collectively, our results demonstrate that deficiency of the LKB1-AMPK axis in cancers reactivates PROX1 to sustain intracellular BCAA pools, resulting in enhanced mTOR signalling, and facilitating tumourigenesis and aggressiveness.

Suggested Citation

  • Yanan Wang & Mengjun Luo & Fan Wang & Yu Tong & Linfeng Li & Yu Shu & Ke Qiao & Lei Zhang & Guoquan Yan & Jing Liu & Hongbin Ji & Youhua Xie & Yonglong Zhang & Wei-Qiang Gao & Yanfeng Liu, 2022. "AMPK induces degradation of the transcriptional repressor PROX1 impairing branched amino acid metabolism and tumourigenesis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34747-y
    DOI: 10.1038/s41467-022-34747-y
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    References listed on IDEAS

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    1. Moritz Middelhoff & Henrik Nienhüser & Giovanni Valenti & H. Carlo Maurer & Yoku Hayakawa & Ryota Takahashi & Woosook Kim & Zhengyu Jiang & Ermanno Malagola & Krystle Cuti & Yagnesh Tailor & Leah B. Z, 2020. "Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Alejo Efeyan & Roberto Zoncu & Steven Chang & Iwona Gumper & Harriet Snitkin & Rachel L. Wolfson & Oktay Kirak & David D. Sabatini & David M. Sabatini, 2013. "Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival," Nature, Nature, vol. 493(7434), pages 679-683, January.
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