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.1 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).2 PKM2 expression is upregulated in human cancer cells.2 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.3 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.4 Importantly, nucleus-localized PKM2 is involved in controlling gene transcription.5 Under hypoxic conditions, PKM2 is hydroxylated at Pro403/408 by prolyl hydroxylase 3, resulting in binding of PKM2 to hypoxia-inducible factor-1α (HIF-1α), which stimulates HIF-1α-dependent transactivation of glycolytic genes that promote glucose metabolism in cancer cells.6 PKM2 was also shown to phosphorylate Stat3 at Tyr705 and induce downstream MAPK25 (formerly MEK5) expression.7 Given the significant role of growth factor receptor protein kinases in tumor progression, important questions are whether and how PKM2 is regulated differently from PKM1 in response to activation of receptor protein kinases and what is the role of PKM2 regulation in tumor development. Our recent studies demonstrated that activation of epidermal growth factor (EGF) receptor (EGFR) results in translocation of PKM2, but not PKM1, into the nucleus in glioblastoma cells, breast cancer cells and prostate cancer cells.5 Mutations and overexpression of EGFR have been detected in many types of human cancer and have been targeted for cancer treatment.5 Intriguingly, EGF stimulation also leads to translocation of both c-Src and β-catenin into the nucleus, where c-Src binds to and phosphorylates β-catenin at Tyr333. Phosphorylated Tyr333 functions as a binding motif for interaction of β-catenin with PKM2. This interaction is required for both proteins, which are in a complex with TCF4, to bind to the CCND1 (encoding for cyclin D1) and MYC promoters, where PKM2 dissociates histone deacetylase 3 (HDAC3) from the promoters and initiates gene expression in a PKM2 kinase activity–dependent manner.5,8 However, a fundamental question remains: what is the exact function of PKM2 in controlling gene promoter activity? Our continuous study recently published in Cell,9 provides an answer. This study demonstrated that PKM2 directly binds to histone H3 (H3.3 variant) and phosphorylates H3 at Thr11 in the presence of phosphoenolpyruvate, the physiological phosphate group donor of PKM2. In contrast, PKM1 is unable to phosphorylate histone H3. Phosphorylation of histone H3 at Thr11 (H3-Thr11 phosphorylation) abrogates the interaction between histone H3 and HDAC3, leading to acetylation of H3 at Thr11-adjacent Lys9. Depletion of PKM2 by expression of PKM2 shRNA blocked EGF-induced H3-Thr11 phosphorylation and H3-Lys9 acetylation at both the CCND1 and MYC promoter regions, which was rescued by reconstituted expression of wild-type PKM2 but not its kinase-dead mutant. These findings indicated that PKM2 kinase activity is required for histone H3 modifications and expression of cyclin D1 and cMYC. Functional studies showed that replacement of endogenous histone H3 with H3-Thr11Ala mutant arrested tumor cells in the G0/G1 phase, inhibited tumor cell proliferation and completely blocked brain tumorigenesis in mice. Immunohistochemistry (IHC) analyses showed that EGFR activation, PKM2 nuclear localization and H3-Thr11 phosphorylation correlate with each other in human primary glioblastoma (GBM) specimens. In addition, IHC analyses showed significantly lower levels of H3-Thr11 phosphorylation in low-grade diffuse astrocytoma [World Health Organization (WHO) grade II; median survival time > 5 y] than in GBM (WHO grade IV). In line with the correlation between nuclear expression level of PKM2 and poor GBM prognosis,5 analyses of survival durations of 85 patients with GBM revealed that patients whose tumors had low H3-Thr11 phosphorylation had a much longer median survival than those whose tumors had high levels of H3-Thr11 phosphorylation, indicating that PKM2-dependent H3-Thr11 phosphorylation can serve as a prognostic marker for patients with GBM.9 In summary, these findings established that whereas PKM2 acts as a glycolytic enzyme for ATP generation and pyruvate production, PKM2 also functions as a protein kinase phosphorylating histone for gene transcription.9 PKM2 directly regulated expression of cyclin D1, which is a key regulator of cell cycle progression, and expression of c-Myc, which can subsequently upregulate glycolytic enzyme gene expression, thereby promoting glycolysis in a feedback manner.9 This nonmetabolic function of PKM2 acting as a histone kinase is essential for tumorigenesis, which provides a molecular basis for improved diagnosis and treatment of tumors.