PKM2 functions as a histone kinase

In the presence of oxygen, most differentiated cells generate the energy needed for cellular processes primarily by metabolizing glucose to carbon dioxide by oxidation of glycolytic pyruvate in the mitochondrial tricarboxylic acid cycle. When oxygen becomes limited, differentiated cells produce large amounts of lactate. In contrast, most cancer cells have increased glucose uptake and metabolize glucose to lactate regardless of the availability of oxygen, a phenomenon discovered by Otto Warburg in 1924 and known as the Warburg effect or aerobic glycolysis. In the glycolysis pathway, pyruvate kinase (PK) is a rate-limiting glycolytic enzyme that catalyzes the conversion of phosphoenolpyruvate and ADP to pyruvate and ATP. PK has four isoforms in mammals: PKL, expressed in liver and kidney; PKR, expressed in erythrocytes; PKM1, predominantly expressed in adult muscle, brain, bladder and fibroblasts; and PKM2, expressed in most cells except for adult muscle cells. The PKM1 and PKM2 isoforms result from mutually exclusive alternative splicing of the PKM (formerly PKM2) pre-mRNA (pre-mRNA) that results in inclusion of either exon 9 (PKM1) or exon 10 (PKM2). PKM2 expression is upregulated in human cancer cells. In human lung cancer cells, replacing PKM2 with PKM1, an isoform with high constitutive activity, inhibits the Warburg effect and tumor formation in nude mouse xenografts. The tumor-specific functions of PKM2 are supported by the finding that oxidation of PKM2 Cys358 leads to inhibition of PKM2 and diversion of glucose flux into the pentose phosphate pathway, thereby generating sufficient reducing potential for detoxification of reactive oxygen species. Importantly, nucleus-localized PKM2 functions as a histone kinase