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

Nat Commun. 2022 Nov 24;13(1):7215. doi: 10.1038/s41467-022-34747-y.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases* / genetics
  • AMP-Activated Protein Kinases* / metabolism
  • Amino Acids
  • Cell Transformation, Neoplastic
  • Humans
  • Neoplasms* / genetics
  • Neoplasms* / metabolism
  • Neoplasms* / pathology
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism

Substances

  • Amino Acids
  • AMP-Activated Protein Kinases
  • TOR Serine-Threonine Kinases
  • Transcription Factors
  • prospero-related homeobox 1 protein