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

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 () and Yanfeng Liu ()
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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
Yonglong Zhang: Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Wei-Qiang Gao: Shanghai Jiao Tong University
Yanfeng Liu: Shanghai Jiao Tong University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34747-y

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