TGF-β-dependent reprogramming of amino acid metabolism induces epithelial-mesenchymal transition in non-small cell lung cancers

Commun Biol. 2021 Jun 24;4(1):782. doi: 10.1038/s42003-021-02323-7.


Epithelial-mesenchymal transition (EMT)-a fundamental process in embryogenesis and wound healing-promotes tumor metastasis and resistance to chemotherapy. While studies have identified signaling components and transcriptional factors responsible in the TGF-β-dependent EMT, whether and how intracellular metabolism is integrated with EMT remains to be fully elucidated. Here, we showed that TGF-β induces reprogramming of intracellular amino acid metabolism, which is necessary to promote EMT in non-small cell lung cancer cells. Combined metabolome and transcriptome analysis identified prolyl 4-hydroxylase α3 (P4HA3), an enzyme implicated in cancer metabolism, to be upregulated during TGF-β stimulation. Further, knockdown of P4HA3 diminished TGF-β-dependent changes in amino acids, EMT, and tumor metastasis. Conversely, manipulation of extracellular amino acids induced EMT-like responses without TGF-β stimulation. These results suggest a previously unappreciated requirement for the reprogramming of amino acid metabolism via P4HA3 for TGF-β-dependent EMT and implicate a P4HA3 inhibitor as a potential therapeutic agent for cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism*
  • Animals
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / drug effects*
  • Female
  • Gene Expression Profiling
  • Humans
  • Lung Neoplasms / pathology*
  • Metabolomics
  • Mice
  • Procollagen-Proline Dioxygenase / physiology
  • Transforming Growth Factor beta / pharmacology*


  • Amino Acids
  • Transforming Growth Factor beta
  • P4HA3 protein, human
  • Procollagen-Proline Dioxygenase