Spermine attenuates TGF-β-induced EMT by downregulating fibronectin

Epithelial-mesenchymal transition (EMT) is a highly dynamic cellular process that occurs in development, tissue repair, and cancer metastasis. As a master EMT inducer, transforming growth factor-beta (TGF-β) can activate the EMT program by regulating the expression of key EMT-related genes and triggering other required cellular changes. However, it is unclear whether cell metabolism is involved in TGF-β-induced EMT. Here, we characterized early metabolic changes in response to transient TGF-β stimulation in HaCaT cells and discovered that TGF-β signaling significantly reduces the intracellular polyamine pool. Exogenous addition of spermine, but not other polyamines, attenuates TGF-β-induced EMT. Mechanistically, spermine downregulates the extracellular matrix protein fibronectin. Furthermore, we found that TGF-β activates extracellular signal-regulated kinase to enhance the expression of spermine oxidase, which is responsible for the reduced spermine concentration. This action of TGF-β on EMT via the polyamine metabolism provides new insights into the mechanisms underlying EMT and might be exploited as a way to target the EMT program for therapy.