PKM2 Phosphorylates Histone H3 and Promotes Gene Transcription and Tumorigenesis

Yang, Weiwei; Xia, Yan; Hawke, David H.; Li, Xinjian; Ji, Liang; Xing, Dongming; Aldape, Kenneth; Hunter, Tony; Yung, W.K. Alfred; Lu, Zhimin

doi:10.1016/j.cell.2012.07.018

Cited by 686 publications

(727 citation statements)

References 41 publications

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“…Thus, we examined whether PKM2 could directly phosphorylate SREBP-1a. For that purpose, we performed in vitro kinase assays using Flag-tagged PKM2 proteins that were overexpressed and immune-purified from HEK293T cell lysates as kinase and recombinant GST-nBP1a proteins as substrate (24). We detected phosphor-threonine signals in recombinant SREBP-1a only when the PKM2 substrate phosphoenolpyruvate (PEP) was added to the reactions (Fig.…”

Section: Pkm2 Regulates Nuclear Srebp-1 Protein Stabilitymentioning

confidence: 99%

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Pyruvate kinase M2 interacts with nuclear sterol regulatory element–binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma

Zhao

Yang

et al. 2018

Journal of Biological Chemistry

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Dysregulation of lipid metabolism is common in cancer cells, but the underlying mechanisms are poorly understood. Sterol regulatory elementbinding proteins (SREBPs) stimulate lipid biosynthesis through transcriptional activation of lipogenic enzymes. However, SREBPs' roles and potential interacting partners in cancer cells are not fully defined. Using a biochemical approach, we found here that pyruvate kinase M2 (PKM2) physically interacts with the nuclear form of SREBP-1a (nBP1a), by binding to amino acids 43-56 in nBP1a. We also found that PKM2 activates SREBP target gene expression and lipid biosynthesis by stabilizing nBP1a proteins. Using a competitive peptide inhibitor to block the formation of the SREBP-1a/PKM2 complex, we observed that this blockade inhibited lipogenic gene expression. Of note, nBP1a phosphorylation at Thr-59 enhanced the binding to PKM2 and promoted cancer cell growth. Moreover, we show that PKM2 phosphorylates Thr-59 in vitro. Lastly, in human patients with hepatocellular carcinoma, nBP1a phosphorylation at Thr-59 was negatively correlated with clinical outcomes. Together, our results reveal that nBP1a/PKM2 interaction activates lipid metabolism genes in cancer cells and that Thr-59 phosphorylation of SREBP-1a plays an important role in cancer cell proliferation.Lipids are essential for cell proliferation. In fact, it has been estimated that more than 90% fatty acids in tumors cells are derived from de novo biosynthesis, while normal cells obtain lipids primarily from the circulation (1). In several types of cancer, including breast and prostate cancer, fatty acid synthase (Fasn) gene is up regulated (2), suggesting that fatty acid biosynthesis may play a role in cancer pathogenesis. Sterol regulatory element-binding proteins (SREBPs) are conserved transcription factors that can activate the transcription of genes encoding the key lipogenic enzymes, including Fasn (3,4). In mammalian cells, there are three SREBP isoforms (SREBP-1a, -1c and -2) encoded by two different genes, Srebf1 and Srebf2 (5). Two distinct promoters generate SREBP1a and SREBP-1c isoforms from the Srebf1 gene (5). Interestingly, Srebf1a is expressed at higher levels in cancer cells as compared to normal tissues, while Srebf1c is the predominant product of Srebf1 in normal tissues (6). In addition, SREBP-1a is a potent transcriptional activator for all known SREBP-target genes (7). The SREBP1 protein levels are often correlated with tumor size, histological grade and metastasis, and SREBP1 loss of function inhibits cell proliferation and induces apoptosis, cell migration and invasion in liver, ovarian and endometrial cancers (8)(9)(10)(11). Furthermore, genetic depletion or pharmacological inhibition of SREBP1 has been shown to suppress the epidermal growth factor receptor (EGFR)-induced glioblastoma (12). Blocking SREBP pathway prevents hepatocellular carcinoma (HCC) in mouse models (13). Thus, SREBP1 is required to support proliferation in some cancer cells.Previous studies have shown that pyruvate kinase isoform M...

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Section: Pkm2 Regulates Nuclear Srebp-1 Protein Stabilitymentioning

confidence: 99%

“…PKM2 has been reported as a threonine/serine kinase of proteins, including histone H3 (24) and MLC2 (25). Thus, we examined whether PKM2 could directly phosphorylate SREBP-1a.…”

Section: Pkm2 Regulates Nuclear Srebp-1 Protein Stabilitymentioning

confidence: 99%

Pyruvate kinase M2 interacts with nuclear sterol regulatory element–binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma

Zhao

Yang

et al. 2018

Journal of Biological Chemistry

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“…Nuclear PKM2 associates with phosphorylated β-catenin upon EGFR activation to promote cyclin D1 (13). PKM2 binds to and phosphorylates Stat3 and histone H3 (17), activating gene transcription and tumorigenesis. Thus, both cytosolic and nuclear PKM2 contribute to altered metabolism and proliferation in cancer.…”

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confidence: 99%

JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α–mediated glucose metabolism

Wang

Hsieh

Cheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

255

220

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JMJD5, a Jumonji C domain-containing dioxygenase, is important for embryonic development and cancer growth. Here, we show that JMJD5 is up-regulated by hypoxia and is crucial for hypoxiainduced cell proliferation. JMJD5 interacts directly with pyruvate kinase muscle isozyme (PKM)2 to modulate metabolic flux in cancer cells. The JMJD5-PKM2 interaction resides at the intersubunit interface region of PKM2, which hinders PKM2 tetramerization and blocks pyruvate kinase activity. This interaction also influences translocation of PKM2 into the nucleus and promotes hypoxiainducible factor (HIF)-1α-mediated transactivation. JMJD5 knockdown inhibits the transcription of the PKM2-HIF-1α target genes involved in glucose metabolism, resulting in a reduction of glucose uptake and lactate secretion in cancer cells. JMJD5, along with PKM2 and HIF-1α, is recruited to the hypoxia response element site in the lactate dehydrogenase A and PKM2 loci and mediates the recruitment of the latter two proteins. Our data uncover a mechanism whereby PKM2 can be regulated by factor-bindinginduced homo/heterooligomeric restructuring, paving the way to cell metabolic reprogram.Warburg effect | aerobic glycolysis | breast cancer | cancer metabolism J MJD5 is a Jumonji C domain-containing dioxygenase shown to be involved in lysine demethylation (1-3) and hydroxylation functions (4). Although the exact cellular substrates and functions of JMJD5 remain unclear, JMJD5 was shown to positively regulate cyclin A1 but negatively regulate p53 and p21 (1-3). Knockdown of JMJD5 in Michigan Cancer Foundation (MCF)-7 cells inhibits cell proliferation (1), and JMJD5 −/− embryos showed severe growth retardation, resulting in embryonic lethality at the midgestation stage (3). These data, together with its general overexpression in tumor tissues, implicate a role of JMJD5 in carcinogenesis. In this paper, we define a role of JMJD5 in regulating tumor metabolism under normoxic and hypoxic conditions through its interaction with pyruvate kinase muscle isozyme (PKM)2.One of the hallmarks of cancer cells is their altered metabolism, referred to as aerobic glycolysis, or the Warburg effect (5). This generally involves an increased uptake of glucose, use of intracellular glucose to pyruvate via glycolysis, and the conversion into lactate in the presence of sufficient oxygen. Along this metabolic flux, PKM1 or its spliced variant, PKM2, which dephosphorylates phosphoenolpyruvate (PEP) into pyruvate, the last step of glycolysis, is an important signal integrator whose activities determine the cytosolic level of pyruvate, thereby affecting subsequent metabolic flow to lactate, tricarboxylic acid cycle or biosynthetic pathway (6). Enzymatically, PKM2, an embryonic isoform found abundantly in tumor cells, is less active than PKM1, which allows the accumulation of glycolytic intermediates and diversion into biosynthetic pathways, demanded by rapid-proliferating cells.As a pivotal regulator of tumor metabolism, PKM2's activity is further modulated by allosteric regulation vi...

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“…On the other hand, non-metabolic function of PKM2, which is mainly associated with the nuclear PKM2, has been identified as a major contributor during tumorigenesis. For example, nuclear PKM2 displays kinase activity in phosphorylating a number of protein substrates, including histone H3 (4,5), signal transducer and activator of transcription 3 (stat3) (6,7), Bub3 (8), and myosin light chain 2 (MLC2) (9), for which PKM2 uses the high-energy phosphate from PEP but not ATP as a phosphate donor. The PKM2-induced phosphorylations of stat3 at tyrosine 705 and histone H3 at threonine 11 respectively activate the transcriptions of MEK5 and endothelial growth factor (EGF)-stimulated cyclin D1, leading to increased tumor cell proliferation.…”

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confidence: 99%

A Novel Role for Pyruvate Kinase M2 as a Corepressor for P53 during the DNA Damage Response in Human Tumor Cells

Wang

et al. 2016

Journal of Biological Chemistry

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Edited by Patrick SungThe pyruvate kinase (PK) is a rate-limiting glycolytic enzyme catalyzing the dephosphorylation of phosphoenolpyruvate to pyruvate, yielding one molecule of ATP. The M2 isoform of PK (PKM2) is predominantly expressed in normal proliferating cells and tumors, and both metabolic and non-metabolic activities for the enzyme in promoting tumor cell proliferation have been identified. However, the exact roles of PKM2 in tumor initiation, growth and maintenance are not yet fully understood. Using immunoprecipitation-coupled LC-MS/MS in MCF7 cells exposed to DNA-damaging agent, we report that the nuclear PKM2 interacts directly with P53 protein, a critical safeguard for genome stability. Specifically, PKM2 inhibits P53-dependent transactivation of the P21 gene by preventing P53 binding to the P21 promoter, leading to a nonstop G 1 phase. As a result, PKM2 expression provides a growth advantage for tumor cells in the presence of a DNA damage stimulus. In addition, PKM2 interferes with phosphorylation of P53 at serine 15, known to stimulate P53 activity by the ATM serine/threonine kinase. These findings reveal a new role for PKM2 in modulating the DNA damage response and illustrate a novel mechanism of PKM2 participating in tumorigenesis.Pyruvate kinase (PK), 4 a rate-limiting enzyme of glycolysis, catalyzes the transfer of phosphate from phosphoenolpyruvate (PEP) to ADP, yielding one molecule of ATP and pyruvate. The PK consists of four isoforms, the PKLR gene-encoded PKL and PKR isoforms and the PKM gene-encoded M1 (PKM1) and M2 (PKM2) isoforms, which express in different types of mammalian cells and tissues. PKM1 constitutively forms stable tetramers (the active form of PK) and is expressed in normal adult tissues that require high levels of energy, such as the heart, brain, and skeletal muscle. In contrast, PKM2 exists in either tetramers or dimers with less activity and metabolic intermediate fructose-1,6-bisphosphate (FBP) can allosterically activate PKM2 by promoting the formation of tetramer from dimer (1, 2). PKM2 is selectively expressed in normal proliferating cells as well as tumor cells, indicating an indispensable role in cancer development.There are two known mechanisms by which PKM2 favors tumor cell growth, one dependent on and one independent of glycolysis. As a glycolytic enzyme, PKM2 in tumor cells shifts glucose metabolism from oxidative phosphorylation to glycolysis under normoxic conditions, a phenomenon termed the Warburg effect or aerobic glycolysis (3). On the other hand, non-metabolic function of PKM2, which is mainly associated with the nuclear PKM2, has been identified as a major contributor during tumorigenesis. For example, nuclear PKM2 displays kinase activity in phosphorylating a number of protein substrates, including histone H3 (4, 5), signal transducer and activator of transcription 3 (stat3) (6, 7), Bub3 (8), and myosin light chain 2 (MLC2) (9), for which PKM2 uses the high-energy phosphate from PEP but not ATP as a phosphate donor. The PKM2-induced phosphorylation...

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PKM2 Phosphorylates Histone H3 and Promotes Gene Transcription and Tumorigenesis

Cited by 686 publications

References 41 publications

Pyruvate kinase M2 interacts with nuclear sterol regulatory element–binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma

Pyruvate kinase M2 interacts with nuclear sterol regulatory element–binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma

JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α–mediated glucose metabolism

A Novel Role for Pyruvate Kinase M2 as a Corepressor for P53 during the DNA Damage Response in Human Tumor Cells

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