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Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

ABSTRACT: Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase, and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2 null mice (Pkm2-/-). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2-/- mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism.

ORGANISM(S): Mus musculus

PROVIDER: GSE79535 | GEO | 2016/03/25

SECONDARY ACCESSION(S): PRJNA316111

REPOSITORIES: GEO

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Similar Datasets

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

Project description:Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase, and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2 null mice (Pkm2-/-). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2-/- mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism. RNA was isolated from flash frozen ground whole liver tissue of 35 week old PKM2 KO and WT mice. Three independent mice from each condition were used as biological replicates.

2016-03-25 | E-GEOD-79535 | biostudies-arrayexpress

Transcript profiling of global PKM2 knockout mouse hearts to evaluate the cardiac role of PKM2 after myocardial infarction

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2024-09-18 | GSE243668 | GEO

Expression data from PKM1 or PKM2 expressing mouse embryonic fibroblasts.

Project description:We profiled global gene expression for two separate lines of mouse embryonic fibroblasts and find that deletion of PKM2 and expression of PKM1 does not alter global gene expression profiles. We used microarrays to futher characterize the effects of PKM1 expression compared to PKM2 expression on global gene expression in mouse embryonic fibroblasts. Primary mouse embryonic fibroblast cells were used for RNA extraction and hybridization on Affymetrix microarrays. Intensity files were RMA normalized using Affymetrix expression console.

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Expression data from PKM1 or PKM2 expressing mouse embryonic fibroblasts.

2015-05-01 | GSE60499 | GEO

The Pkm duet: Coordinating C2C12 myoblast proliferation and differentiation through Histone 3 phosphorylation and cBAF complex dynamics

Project description:Pkm1 and Pkm2 kinases are expressed in differentiating skeletal myoblasts. Knockdown of Pkm1 or Pkm2, therefore, can affect myoblast differentiation, by two independent regulatory mechanisms involving histone phosphorylation and chromatin remodeling complexes. Pkm2 KD in C2C12 cells reduced the chromatin marks of phosphorylated H3-T6, H3-T11 and H3-T45 into several essential myogenic promoters, and consequently, prevented their expression. Also, the transcriptional analysis demonstrated that Pkm2 is required for the expression of the cBAF-specific subunits Dpf2 and Baf250a, which we have previously demonstrated are essential for myogenesis. In contrast, Pkm1 KD alters the localization of nuclear Dpf2 into the cytoplasm as well. Mechanistically, Pkm KD resulted in decreased binding of cBAF components to their myogenic target genes, which also suggested a positive regulation between the cBaf complex and the H3 phosphorylation marks.

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Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation.

Project description:Allosteric regulation is central to the role of the glycolytic enzyme pyruvate kinase M2 (PKM2) in cancer metabolism. Multiple activating and inhibitory allosteric ligands regulate PKM2 activity by controlling the equilibrium between high activity tetramers and low activity dimers and monomers. However, how allosteric inputs from simultaneous binding of different ligands are integrated to regulate PKM2 activity remains elusive. Here, we show that, [PKM2 activation and tetramerisation can be uncoupled as] in the presence of the allosteric inhibitor phenylalanine (Phe), saturating amounts of the activator fructose 1,6-bisphosphate (F-1,6-bP) can induce PKM2 tetramerisation, but fail to maximally increase enzymatic activity. We use a new computational framework to identify residues that mediate FBP-induced allostery and show that, while mutation of A327 and C358 do not abrogate the ability of F-1,6-BP to increase PKM2 activity, it prevents Phe from interfering with it. Our findings demonstrate a role for residues involved in FBP allostery in enabling the integration of allosteric input from Phe and reveal an allosteric cross-talk that underlies the co-ordinate regulation of PKM2 activity by distinct allosteric ligands. The absolute amount of the isoforms of PKM (PKM1/2) were quantified in the cell lines of interested to inform the described model.

2019-11-12 | PXD010334 | Pride

RBMX suppresses tumorigenicity and progression of bladder cancer via interaction with hnRNP A1 protein to regulate PKM alternative splicing

Project description:Bladder cancer (BCa) is one of the most common malignant tumors of urinary system and has high incidence rate and mortality but there is a lack of effective treatment. Therefore, an in-depth study of the molecular mechanisms involved in BCa is of great significance for improving the survival of patients with advanced BCa. We found that the expression of RBMX was significantly declined in BCa, especially in muscle-invasive BCa. BCa patients with low levels of RBMX had poor prognoses. By in vitro and in vivo experiments, RBMX was shown to inhibit BCa cells growth and metastasis. Co-IP coupled with MS and GO analysis identified hnRNP A1 as a RBMX-binding protein. Mechanistically, RBMX competitively bond to the RGG box of hnRNP A1 and antagonized the hnRNP A1-mediated regulation of PKM splicing by blocking the binding of the RGG motif of hnRNP A1 to the sequences flanking PKM exon 9, resulting in downregulation of PKM2 and upregulation of PKM1. By decreasing the PKM2/PKM1 ratio, RBMX suppressed BCa cells aerobic glycolysis, which further inhibited tumorigenicity and progression of BCa.

2020-11-23 | GSE150548 | GEO

CD28-CBCA driven PKM splicing licenses CD8 T cell glycolysis and effector function

Project description:T cells stimulated in the absence of CD28 costimulation are functionally anergic, characterized by reduced glucose metabolism and ability to produce effector cytokines. Surprisingly, previous studies have shown relatively few CD28-specific changes in gene transcription upon costimulation. Using mice expressing mutations in the CD28 cytoplasmic tail, we show a major effect of CD28 costimulation is alternative splicing of numerous genes including the glycolytic enzyme pyruvate kinase (Pkm), which is preferentially spliced from Pkm1 to Pkm2 upon stimulation. PKM2 is dispensable for T cell activation, but necessary for CD8+ T cells to utilize aerobic glycolysis, produce effector cytokines, and provide anti-tumor immunity. Mechanistically, CD28 regulates expression of the Cap-Binding Complex adaptor protein ARS2, which binds Pkm splicing factors and facilitates their interaction with the elongating transcript. Data suggest a major function of CD28 costimulation is control of RNA biogenesis in support of T cell transcriptome remodeling and acquisition of effector function.

2023-09-01 | GSE168824 | GEO

Pyruvate kinase M1 and M2 isoform knock in ES cells differentiate into three germ layers

Project description:Analysis of wild type, PKm1 KI, and PKm2 KI ES cells.

2017-03-08 | GSE57504 | GEO

MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation

Project description:Altered glycolysis is the most fundamental metabolic change associated with the Warburg effect. However, the precise mechanisms are not completely understood. Here we dissect how MNX1-AS1 reinforces the Warburg effect through facilitating the non-glycolytic actions of PKM2 in the nucleus. We found that MNX1-AS1 expression was frequently overexpressed in hepatocellular carcinoma (HCC). In the context of HCC, we show MNX1-AS1 acts as a scaffold to promote interactions between PKM2 and importin α5. Upon EGFR activation, the resulting ternary complex drives the translocation of PKM2 into the nucleus. In consequence, glycolytic pathway components including key mediators of the Warburg effect (LDHA, Glut1 and PDK1) are upregulated. Manipulating MNX1-AS1 elicited robust effects on glycolysis associated with marked changes in HCC growth in vitro and in vivo, indicative of the significant contribution of MNX1-AS1 to tumorigenesis. Moreover, while MNX1-AS1 expression is driven by c-Myc, its actions associated with PKM2 were shown to be downstream and independent of c-Myc. Given the status of MNX1-AS1 as a pan-cancer upregulated lncRNA, this implicitly highlights the potential of targeting MNX1-AS1 to selectively counter the Warburg effect in a range of tumor types.

2022-11-23 | GSE213064 | GEO

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