Pyruvate Kinase M2 Phosphorylates Histone H3

The M2 isoform of pyruvate kinase (PKM2) is overexpressed in human cancers and is required for aerobic glycolysis, also known as the Warburg effect. PKM2 also can directly regulate gene expression, as a recent study has shown that PKM2 translocates to the nucleus, forms a complex with β-catenin, and binds the cyclin D1 (CCND1) and MYC promoters to promote transcription in response to epidermal growth factor receptor (EGFR) activation. Yang and colleagues showed that following stimulation of glioblastoma multiforme (GBM) cells with EGF, PKM2 directly binds histone H3 and phosphorylates it on threonine 11 (T11), which is required for dissociation of histone deacetylase 3 (HDAC3) and subsequent acetylation of histone 3 lysine 9 (K9) at the CCND1 and MYC promoters. PKM2-dependent T11 phosphorylation was thus required for EGF-induced CCND1 and MYC expression, as well as for cell-cycle progression and cell proliferation. Strikingly, mutation of T11 to alanine in GBM cells driven by a constitutively active EGFRvIII mutant completely blocked tumor growth in mice following intracranial injection, indicating that phosphorylation of H3-T11 by PKM2 plays a critical role in GBM development. Consistent with these observations in cell culture and animal models, H3-T11 phosphorylation levels were correlated with EGFR activation and nuclear PKM2 expression in primary human GBM samples and were significantly higher in GBM than in low-grade gliomas. Furthermore, patients whose tumors had high levels of H3-T11 phosphorylation had a significantly lower median survival, and H3-T11 levels were an independent predictor of survival. Although it remains to be shown whether PKM2-dependent H3-T11 phosphorylation contributes to the development of other tumor types that are not addicted to EGFR, this study suggests that PKM2-mediated gene regulation is a key contributor to gliomagenesis.

Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, et al. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 2012;150:685-96.