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Mnt Represses Epithelial Identity To Promote Epithelial to Mesenchymal Transition

ABSTRACT: The multi-step process of epithelial to mesenchymal transition (EMT), whereby static epithelial cells become migratory mesenchymal cells, is heavily involved in development, wound healing, and disease states. Despite the major involvement of basic helix-loop-helix (bHLH) transcription factors (TFs) in cell-fate determination, few have examined them for their involvement in fundamental processes that require EMT. Here, we have identified Max network transcription repressor (MNT) as a potent EMT promoting TF in mammary epithelium. We show that depletion of MNT blocked TGF?-induced phenotypic changes, and transcriptomic analysis revealed that MNT is a transcription repressor of epithelial identity. We show that MNT mediates repression of epithelial identity via direct interaction with HDAC1. Lastly, we show that MNT and its target genes are heavily expressed in EMT-High breast cancer, with MNT required for breast cancer cell migration. Taken together, these findings establish MNT as a critical regulator of cell-fate determination and the EMT transcriptome.

ORGANISM(S): Mus musculus

PROVIDER: GSE158546 | GEO | 2021/09/29

REPOSITORIES: GEO

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Project description:Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial-mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of PFKP (phosphofructokinase, platelet), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP.Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial-mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of PFKP (phosphofructokinase, platelet), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP.

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Mnt Represses Epithelial Identity To Promote Epithelial to Mesenchymal Transition

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