Tissue-specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers

Desai, Shruti; Ding, Minming; Wang, Bin; Lu, Zhimin; Zhao, Qi; Shaw, Kenna; Yung, W.K. Alfred; Weinstein, John N.; Tan, Ming; Yao, Jun

doi:10.18632/oncotarget.1159

Cited by 139 publications

(125 citation statements)

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“…Analyses of The Cancer Genome Atlas DNA methylation data have revealed that elevated PKM2 expression correlates well with a hypomethylation status of intron 1 of the PKM gene in multiple cancer types, suggesting that epigenetic regulation by DNA methylation is an important mechanism in controlling PKM transcription in tumors (Desai et al, 2014).…”

Section: Regulation Of Pkm2 Expressionmentioning

confidence: 99%

“…It is also worth noting that PKM2 expression levels vary among different types of cancer cells (Desai et al, 2014), suggesting that the role of PKM2 in tumorigenesis depends on the signaling context. For instance, recent reports showed that PKM2 deficiency in mice did not block Brca1-loss-driven mammary tumor formation but did inhibit cyclin D1 expression and leukemia initiation that is induced by the fusion proteins BCR-ABL and MLL-AF9 (Israelsen et al, 2013;Wang et al, 2014b).…”

Section: Pkm2 As a Molecular Target For Cancer Treatmentmentioning

confidence: 99%

“…PKM1 is highly expressed in normal tissues, whereas PKM2 expression is also detected in normal tissues, including those from lung, liver, colon, thyroid, kidney and bladder (Bluemlein et al, 2011;Yang and Lu, 2013b). Analyses of 16 tumor types using the cancer genome atlas RNASeq and exon array datasets has revealed that an isoform switch from PKM1 to PKM2 occurs in glioblastomas (Desai et al, 2014). Despite a lack of isoform switches in other tumor types, PKM2 expression has been found to be increased in all cancer types examined (Bluemlein et al, 2011;Desai et al, 2014), and replacement of PKM2 with PKM1 has been found to inhibit aerobic glycolysis and tumor growth (Christofk et al, 2008a;Gumińska et al, 1988;Mellati et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

“…Analyses of 16 tumor types using the cancer genome atlas RNASeq and exon array datasets has revealed that an isoform switch from PKM1 to PKM2 occurs in glioblastomas (Desai et al, 2014). Despite a lack of isoform switches in other tumor types, PKM2 expression has been found to be increased in all cancer types examined (Bluemlein et al, 2011;Desai et al, 2014), and replacement of PKM2 with PKM1 has been found to inhibit aerobic glycolysis and tumor growth (Christofk et al, 2008a;Gumińska et al, 1988;Mellati et al, 1992). These findings point to a crucial role for expression of PKM2 in tumor growth.…”

Section: Introductionmentioning

confidence: 99%

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Pyruvate kinase M2 at a glance

Yang

2015

Journal of Cell Science

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Reprogrammed metabolism is a key feature of cancer cells. The pyruvate kinase M2 (PKM2) isoform, which is commonly upregulated in many human cancers, has been recently shown to play a crucial role in metabolism reprogramming, gene transcription and cell cycle progression. In this Cell Science at a glance article and accompanying poster, we provide a brief overview of recent advances in understanding the mechanisms underlying the regulation of PKM2 expression, enzymatic activity, metabolic functions and subcellular location. We highlight the instrumental role of the non-metabolic functions of PKM2 in tumorigenesis and evaluate the potential to target PKM2 for cancer treatment.

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Section: Regulation Of Pkm2 Expressionmentioning

confidence: 99%

Section: Pkm2 As a Molecular Target For Cancer Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pyruvate kinase M2 at a glance

Yang

2015

Journal of Cell Science

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157

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“…PKM2 and its isoform PKM1 are products of the Pkm gene through alternative splicing (15). It has been reported that in most tumors the Pkm2 mRNA is elevated (16,17) and in some cases the Pkm gene expression is switched from Pkm1 to Pkm2 (17). Several studies have revealed that PKM2 can translocate into nucleus and acts as a transcriptional cofactor to promote tumor development (18)(19)(20).…”

mentioning

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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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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FOXM1D potentiates PKM2‐mediated tumor glycolysis and angiogenesis

Zhang

Huang

et al. 2021

Molecular Oncology

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Tumor growth, especially in the late stage, requires adequate nutrients and rich vasculature, in which PKM2 plays a convergent role. It has been reported that PKM2, together with FOXM1D, is upregulated in late-stage colorectal cancer and associated with metastasis; however, their underlying mechanism for promoting tumor progression remains elusive. Herein, we revealed that FOXM1D potentiates PKM2-mediated glycolysis and angiogenesis through multiple protein-protein interactions. In the presence of FBP, FOXM1D binds to tetrameric PKM2 and assembles a heterooctamer, restraining PKM2 metabolic activity by about a half and thereby promoting aerobic glycolysis. Furthermore, FOXM1D interacts with PKM2 and NF-jB and induces their nuclear translocation with the assistance of the nuclear transporter importin 4. Once in the nucleus, PKM2 and NF-jB complexes subsequently augment VEGFA transcription. The increased VEGFA is secreted extracellularly via exosomes, an event potentiated by the interaction of FOXM1 with VPS11, eventually promoting tumor angiogenesis. Based on these findings, our study provides another insight into the role of PKM2 in the regulation of glycolysis and angiogenesis.

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Tissue-specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers

Cited by 139 publications

References 24 publications

Pyruvate kinase M2 at a glance

Pyruvate kinase M2 at a glance

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

FOXM1D potentiates PKM2‐mediated tumor glycolysis and angiogenesis

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