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Role of NuRD subunits CHD3 and CHD4 in human melanoma cells (RNA-seq)

ABSTRACT: The Nuclesome Remodelling and Deacetylation (NuRD) complex is an epigenetic regulator of gene expression comprising two mutually exclusive ATPase subunits CHD3 or CHD4. Here we show that CHD4 silencing in multiple types of cancer cells de-represses expression of the PADI1 (Protein Arginine Deiminase 1) and PADI3 enzymes that convert arginine to citrulline. Increased PADI1 and PADI3 expression enhances citrullination of three arginines of the key glycolytic regulatory enzyme PKM2 (pyruvate kinase) promoting excessive glycolysis, lowered ATP levels and slowed proliferation. PKM2 citrullination lowers its sensitivity to the allosteric inhibitors Tryptophan and Phenylalanine shifting equilibrium towards the allosteric activator Serine, thereby bypassing the normal physiological regulation of glycolysis by low Serine levels. Our results describe a novel pathway linking epigenetic regulation of PADI1 and PAD3 expression by CHD4 to glycolytic flux and the control of cancer cell growth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134849 | GEO | 2019/11/03

REPOSITORIES: GEO

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Role of NuRD subunits CHD3 and CHD4 in human melanoma cells (ChIP-seq)

Project description:The Nuclesome Remodelling and Deacetylation (NuRD) complex is an epigenetic regulator of gene expression comprising two mutually exclusive ATPase subunits CHD3 or CHD4. Here we show that CHD4 silencing in multiple types of cancer cells de-represses expression of the PADI1 (Protein Arginine Deiminase 1) and PADI3 enzymes that convert arginine to citrulline. Increased PADI1 and PADI3 expression enhances citrullination of three arginines of the key glycolytic regulatory enzyme PKM2 (pyruvate kinase) promoting excessive glycolysis, lowered ATP levels and slowed proliferation. PKM2 citrullination lowers its sensitivity to the allosteric inhibitors Tryptophan and Phenylalanine shifting equilibrium towards the allosteric activator Serine, thereby bypassing the normal physiological regulation of glycolysis by low Serine levels. Our results describe a novel pathway linking epigenetic regulation of PADI1 and PAD3 expression by CHD4 to glycolytic flux and the control of cancer cell growth.

2019-11-03 | GSE134848 | GEO

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

Small molecule activation of PKM in cancer cells induces serine auxotrophy

Project description:Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM isoform, effectively constraining lower glycolysis. Here, we report the discovery of novel PKM activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the non-essential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress. A549 cancer cells were treated with compound-16 for up to 24 hours in the presence and absence of serine in the media.

2012-12-20 | E-GEOD-40191 | biostudies-arrayexpress

IP-MS detected the interation proteins of PHGDH

Project description:Vascular endothelial cells (ECs) senescence correlates with the increase of cardiovascular diseases in ageing population. Although ECs rely glycolysis for energy production, little is known about the role of glycolysis in ECs senescence. Here, we report a critical role for glycolysis-derived serine biosynthesis in preventing ECs senescence. During senescence, the expression of serine biosynthetic enzyme PHGDH is significantly reduced due to decreased transcription of the activating transcription factor ATF4, which leads to decreased intracellular serine. PHGDH prevents premature senescence primarily by enhancing the stability and activity of pyruvate kinase M2 (PKM2). Mechanistically, PHGDH interacts with PKM2, which prevents PCAF-catalyzed PKM2 K305 acetylation and subsequent degradation by autophagy. In addition, PHGDH facilitates p300-catalyzed PKM2 K433 acetylation, which promotes PKM2 nuclear translocation and stimulates its activity to phosphorylate H3T11 and regulate the transcription of senescence-associated genes. Vascular endothelium-targeted expression of PHGDH and PKM2 ameliorates the mice ageing phenotype. Our findings reveal that enhancing serine biosynthesis could become a novel therapy to promote healthy ageing.

2023-05-10 | PXD035586 | Pride

IP-MS detected the interation protein with PKM2

2023-05-10 | PXD035585 | Pride

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

Small molecule activation of PKM in cancer cells induces serine auxotrophy

2012-12-20 | GSE40191 | GEO

PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis

Project description:Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked. By interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP3Rs), methylated PKM2 inhibits the influx of calcium from the endoplasmic reticulum to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis. Collectively, the CARM1-PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP3R-dependent mitochondrial functions.

2021-07-30 | MTBLS533 | MetaboLights

Transcriptional profiling of PADI4 overexpression and inhibition in mouse embryonic stem cells

Project description:The enzymatic activity of PADI4 was investigated by overexpression and chemical inhibition to determine the effects of arginine citrullination on histone displacement, reprogramming efficiency and the maintenance of pluripotent stem cells.

2013-11-22 | E-MTAB-1975 | biostudies-arrayexpress

Pyruvate kinase M2 controls lipid homeostasis via regulation of SREBPs activation and intestinal cholesterol absorption

Project description:The pyruvate kinase M2 isoform (PKM2) is preferentially expressed in cancer to regulate anabolic metabolism. However, the metabolic requirements of PKM2 in tumorigenesis have yielded contradictory results. Herein we discovered that this glycolytic enzyme regulates lipid homeostasis in cancer cell autonomous manner and at systemic levels. Transmembrane protein 33 (TMEM33) was identified as a downstream effector of PKM2, whose expression level positively correlates with plasma total cholesterol level in vivo. Loss of PKM2 leads to up-regulation of TMEM33, which recruits ring finger protein 5 (RNF5) to promote SCAP ubiquitination and degradation, thereby inhibiting Golgi translocation and activation of sterol regulatory element binding protein 1 (SREBP1). Moreover, global PKM2 knockout promoted allografted tumor growth, at least partially attributes to the elevated plasma cholesterol level caused by increased intestinal Niemann-Pick C1-Like 1 (NPC1L1) to facilitate cholesterol absorption. Collectively, PKM2-TMEM33 axis modulates cell autonomous lipid metabolism by regulating SREBP activation. PKM2 in small intestine plays critical functions in controlling systemic cholesterol level. Overall, our results underscore unappreciated functions of PKM2 in lipid homeostasis and imply that combining an allosteric activator of PKM2 with NPC1L1 inhibitor represents a therapeutic invention for cancer treatment.

2021-08-06 | PXD026434 | Pride

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