Significance Our study shows that pyruvate kinase M2 (PKM2), an alternatively spliced variant of the pyruvate kinase gene, mediates epithelial–mesenchymal transition (EMT), which is critical for cancer cells to acquire invasive potential. Our study demonstrates that EMT stimulates nuclear translocation of PKM2 and decreases epithelial cadherin transcription (a requirement for EMT induction). Our results also demonstrate that PKM2 interacts with the transcriptional factor TGF-β–induced factor homeobox 2, which induces the deacetylation of histone H3, resulting in repressed E-cadherin expression. The precise understanding of nuclear PKM2 function suggests the potential for a model preventing cancer metastasis.