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

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-beta-dependent EMT, whether and how intracellular metabolism is integrated with EMT remains to be fully elucidated. Here, we showed that TGF-beta 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 alpha 3 (P4HA3), an enzyme implicated in cancer metabolism, to be upregulated during TGF-beta stimulation. Further, knockdown of P4HA3 diminished TGF-beta-dependent changes in amino acids, EMT, and tumor metastasis. Conversely, manipulation of extracellular amino acids induced EMT-like responses without TGF-beta stimulation. These results suggest a previously unappreciated requirement for the reprogramming of amino acid metabolism via P4HA3 for TGF-beta-dependent EMT and implicate a P4HA3 inhibitor as a potential therapeutic agent for cancer. Through metabolome and transcriptome analyses, Nakasuka et al find that TGF-beta-induced epithelial-mesenchymal transition (EMT) in non-small cell lung cancer cells is associated with reprogramming of amino acid metabolism. They also identify P4HA3 as a key enzyme involved in these changes altogether providing insights into potential mechanisms of metastasis.

Automated summary

Through metabolome and transcriptome analyses, Nakasuka et al find that TGF-beta-induced epithelial-mesenchymal transition (EMT) in non-small cell lung cancer cells is associated with reprogramming of amino acid metabolism. They also identify P4HA3 as a key enzyme involved in these changes altogether providing insights into potential mechanisms of metastasis.