The study investigates the role of heterogeneous nuclear ribonucleoprotein (hnRNP) proteins in regulating the alternative splicing of the pyruvate kinase (PKM) gene, which is crucial for aerobic glycolysis in cancer cells. The researchers found that three hnRNP proteins—polypyrimidine tract binding protein (PTB), hnRNPA1, and hnRNPA2—bind to sequences flanking exon 9 of the PKM gene, repressing its inclusion and promoting the inclusion of exon 10, which results in the production of the PKM2 isoform. These proteins are upregulated by the oncogenic transcription factor c-Myc, which is also overexpressed in human gliomas. The study demonstrates that depletion of PTB, hnRNPA1, and hnRNPA2 leads to an increase in the PKM1 isoform, and that their expression correlates with PKM2 levels in both differentiating C2C12 cells and human glioma tumors. These findings highlight a critical pathway that regulates PKM splicing and is essential for tumor cell proliferation.The study investigates the role of heterogeneous nuclear ribonucleoprotein (hnRNP) proteins in regulating the alternative splicing of the pyruvate kinase (PKM) gene, which is crucial for aerobic glycolysis in cancer cells. The researchers found that three hnRNP proteins—polypyrimidine tract binding protein (PTB), hnRNPA1, and hnRNPA2—bind to sequences flanking exon 9 of the PKM gene, repressing its inclusion and promoting the inclusion of exon 10, which results in the production of the PKM2 isoform. These proteins are upregulated by the oncogenic transcription factor c-Myc, which is also overexpressed in human gliomas. The study demonstrates that depletion of PTB, hnRNPA1, and hnRNPA2 leads to an increase in the PKM1 isoform, and that their expression correlates with PKM2 levels in both differentiating C2C12 cells and human glioma tumors. These findings highlight a critical pathway that regulates PKM splicing and is essential for tumor cell proliferation.