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ARID1A Loss Promotes Lung Adenocarcinoma by Remodeling Chromatin Accessibility and Activating Glycolytic Reprogramming

ABSTRACT: This study demonstrated that ARID1A loss markedly promotes lung tumorigenesis in genetic mice models. RNA sequencing reveals significant enrichment of the glycolytic pathway in ARID1A-deficient tumors, which is characterized by the upregulation of PGAM1, PKM2, and PGK1. Besides, ARID1A depletion increases chromatin accessibility and enhances the binding ability of Hif-1a to the promoter regions of Pgam1, Pkm, and Pgk1. In patients with lung cancer, ARID1A status is negatively correlated with mRNA level of PGAM1, PKM, and PGK1.

ORGANISM(S): Mus musculus

PROVIDER: GSE164810 | GEO | 2022/10/01

REPOSITORIES: GEO

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Long noncoding RNA glycoLINC assembles a lower glycolytic complex essential for cellular adaptation to serine starvation

Project description:Here we show that a c-Myc-responsive long noncoding RNA (lncRNA) that we name glycoLINC (gLINC) acts as a backbone for metabolon formation between all four glycolytic pay-off phase enzymes (PGK1, PGAM1, ENO1 and PKM2) along with LDHA.

2020-11-03 | GSE159536 | GEO

PKM2 functions as a histidine kinase to phosphorylate PGAM1 to increase glycolysis shunts in cancer-Cellular lipid level assessment

Project description:Phosphoglycerate mutase 1 (PGAM1) is a key node enzyme that diverts the metabolic reactions from glycolysis into its shunts to support macromolecule biosynthesis for rapid and sustainable cell proliferation. It is prevalent that PGAM1 activity is upregulated in various tumors; however, the underlying mechanism remains unclear. Here, we unveil that pyruvate kinase M2 (PKM2) moonlights as a histidine kinase in a phosphoenolpyruvate (PEP)-dependent manner to catalyze PGAM1 H11 phosphorylation, that is essential for PGAM1 activity. Moreover, monomeric and dimeric PKM2 are efficient to phosphorylate and activate PGAM1, while the tetrameric PKM2 is not. In response to epidermal growth factor (EGF) signaling, Src-catalyzed PGAM1 Y119 phosphorylation is a prerequisite for PKM2 binding and the subsequent PGAM1 H11 phosphorylation, which constitutes the discrepancy between tumor cells and normal ones. A PGAM1-derived pY119-containing cell-permeable peptide or Y119 mutation disrupted the interaction of PGAM1 with PKM2 and its H11 phosphorylation, and eventually dampened the glycolysis shunts and tumor growth. We not only identified a function of PKM2 as a histidine kinase, but also illustrated an enzymes-cross-talk regulatory mode during metabolic reprogramming.

2024-03-21 | PXD049310 | Pride

PKM2 functions as a histidine kinase to phosphorylate PGAM1 to increase glycolysis shunts in cancer

Project description:Phosphoglycerate mutase 1 (PGAM1) is a key-node enzyme that diverts the metabolic intermediates from glycolysis into its shunts to support macromolecule biosynthesis for rapid and sustainable cell proliferation. It is prevalent that PGAM1 activity is upregulated in various tumors; however, the underlying mechanism remains unclear. Here, we unveil that pyruvate kinase M2 (PKM2) moonlights as a histidine kinase in a phosphoenolpyruvate (PEP)-dependent manner to catalyze PGAM1 H11 phosphorylation, that is essential for PGAM1 activity. Moreover, the dimeric or monomeric PKM2 in tumor cells phosphorylates PGAM1 more efficiently than the tetrameric one. In response to epidermal growth factor (EGF), Src signaling triggered PGAM1 Y119 phosphorylation is a prerequisite for PKM2 binding and the subsequent H11 phosphorylation of PGAM1, which constitutes the discrepancy between tumor cells and normal ones. A PGAM1-derived pY119-containing cell-permeable peptide or Y119 mutation disrupts the interaction of PGAM1 with PKM2 and its H11 phosphorylation, and eventually dampens the glycolysis shunts and tumor growth. We not only identifes a histidine kinase function of PKM2, but also illustrates an enzymes-cross-talk regulatory mode during metabolic reprogramming.

2024-03-21 | PXD049235 | Pride

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

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

ARID1A regulates chromatin organization and establishment of epigenetic marks for DSB repair and transcription silencing

Project description:AT-rich interactive domain-containing protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. ARID1A contributes to DNA damage response pathways, and we previously reported that ARID1A loss is associated with mutational signatures linked to DNA repair defects. Here we show that ARID1A is promoting both DNA double-strand breaks (DSBs) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). ARID1A is accumulated at DSBs after DNA damage and regulates the chromatin loop formation at DSB sites by interacting with the cohesin subunit RAD21 and CTCF insulator protein promoting their enrichment around the DSBs. Further analysis demonstrates that ARID1A’s involvement in DSB repair is accompanied by alterations of chromatin accessibility and distribution of activating histone marks at DSBs. ARID1A binds to and promotes the recruitment of the HDAC1 to control transcription repression at these DSBs. Altogether, ARID1A simultaneously regulates DSB repair and transcription silencing in transcriptionally active chromatin. ARID1A depletion resulted in defective DSB repair, which subsequently led to accumulation of micronuclei, activation of cGAS-STING pathway and an increased expression of immunomodulatory cytokines and chemokines upon IR treatment. Furthermore, low ARID1A expression in cancer patients receiving radiotherapy was associated with higher infiltration of several immune cells. The high mutation rate of ARID1A in various cancer types highlights its clinical relevance as a promising biomarker that correlates with the level of immune regulatory cytokines and can estimate the levels of tumor-infiltrating immune cells and response to combination of radio- and immunotherapy.

2024-06-22 | PXD047225 | Pride

Proteomic analysis reveals the role of ARID1A in regulating the Wnt signaling pathway in colon cancer cells

Project description:The AT-rich interacting domain-containing protein 1A (ARID1A) is a tumor suppressor gene that has been implicated in various cancers, including colorectal cancer (CRC). The present study employed a proteomic approach to uncover the molecular mechanisms of ARID1A in CRC carcinogenesis.

2024-05-21 | PXD052413 | JPOST Repository

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

2016-03-25 | GSE79535 | GEO

DNA methylation statuses in ARID1A KO cells

Project description:The CpG island methylator phenotype (CIMP) is associated with prognosis and drug sensitivity in multiple cancer types. In gastric cancer, the CIMP is closely associated with Epstein-Barr virus (EBV) infection and AT-rich interactive domain 1A (ARID1A) mutations, a component of the SWI/SNF chromatin remodeling complex. However, the involvement of SWI/SNF defects in CIMP induction has been unclear. In this study, we demonstrate a causal role of ARID1A loss-of-function in CIMP induction. Mutations of SWI/SNF components, especially ARID1A, was associated with the CIMP, as well as EBV infection, in gastric cancers, and also in uterine endometrial and colorectal cancers, which are not affected by EBV infection. Genome-wide DNA methylation analysis showed that ARID1A knockout (KO) in cultured 293FT cells and gastric epithelial cells, GES1, induced aberrant DNA methylation of a substantial number of CpG sites. DNA methylation was induced at genomic regions with high levels of pre-existing histone H3 lysine 27 trimethylation (H3K27me3) and those with acquired H3K27me3 by ARID1A KO. These results showed that the ARID1A mutation induced aberrant DNA methylation, and this is likely to be one of the potential mechanisms of CIMP induction. (See GSE188293 for data of GES1 with ARID1A KO.)

2022-10-31 | GSE165239 | GEO

mRNA-seq for HCT116 Parental and ARID1A knockdown cells, mRNA-seq for DLD1 Parental, ARID1A knockdown and ARID1A knockout cells, mRNA-seq for COLO320DM Parental and ARID1A knockdown and ARID1A knockout cells

Project description:The study identifies genes that are regulated by the loss of the chromatin remodeller subunit ARID1A in colorectal cancer cell lines. This gene is frequently mutated in colorectal cancer.

2019-06-11 | E-MTAB-7791 | biostudies-arrayexpress

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