SHP2 mutations promote glycolysis and inhibit apoptosis via PKM2/hnRNPK signaling in colorectal cancer

Colorectal cancer (CRC) is one of the most common gastrointestinal tumors. Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) mutations occur in human solid tumors, including CRC. However, the function and underlying mechanism in CRC have not been well characterized. We demonstrated that the SHP2^D61Y and SHP2^E76K mutations occurred in CRC tissues, and these mutations promoted CRC cell proliferation, migration/invasion, and reduced CDDP-induced cell apoptosis in vitro and in vivo. Mechanistically, SHP2^D61Y and SHP2^E76K promote glycolysis by accelerating pyruvate kinase M2 (PKM2) nuclear translocation through mechanism beyond ERK activation. PKM2-IN-1 attenuates PKM2-dependent glycolysis and reduce glucose uptake, lactate production, and ATP levels promoted by SHP2D^61Y and SHP2^E76K in CRC cells. Furthermore, PKM2 upregulates heterogeneous nuclear ribonucleoprotein K (hnRNPK) expression and increases CRC cell proliferation and migration/invasion via regulating hnRNPK ubiquitination. These findings provide evidence that SHP2^D61Y and SHP2^E76K regulate CDDP-induced apoptosis, glucose metabolism, and CRC migration/invasion through PKM2 nuclear translocation and PKM2/hnRNPK signaling.