title: Chaetocin-induced ROS-mediated apoptosis involves ATM-YAP1 axis and JNK-dependent inhibition of glucose metabolism.
abstract: Oxidative stress serves as an important regulator of both apoptosis and metabolic reprogramming in tumor cells. Chaetocin, a histone methyltransferase inhibitor, is known to induce ROS generation. As elevating basal ROS level sensitizes glioma cells to apoptosis, the ability of Chaetocin in regulating apoptotic and metabolic adaptive responses in glioma was investigated. Chaetocin induced glioma cell apoptosis in a ROS-dependent manner. Increased intracellular ROS induced (i) Yes-associated protein 1 (YAP1) expression independent of the canonical Hippo pathway as well as (ii) ATM and JNK activation. Increased interaction of YAP1 with p73 and p300 induced apoptosis in an ATM-dependent manner. Chaetocin induced JNK modulated several metabolic parameters like glucose uptake, lactate production, ATP generation, and activity of glycolytic enzymes hexokinase and pyruvate kinase. However, JNK had no effect on ATM or YAP1 expression. Coherent with the in vitro findings, Chaetocin reduced tumor burden in heterotypic xenograft glioma mouse model. Chaetocin-treated tumors exhibited heightened ROS, pATM, YAP1 and pJNK levels. Our study highlights the coordinated control of glioma cell proliferation and metabolism by ROS through (i) ATM-YAP1-driven apoptotic pathway and (ii) JNK-regulated metabolic adaptation. The elucidation of these newfound connections and the roles played by ROS to simultaneously shift metabolic program and induce apoptosis could provide insights toward the development of new anti-glioma strategies.
authors.affiliation: Cellular and Molecular Neuroscience Division, National Brain Research Centre, Nainwal Mode, Manesar, Gurgaon, Haryana 122051, India.
authors.forename: D
authors.initials: D
authors.lastname: Dixit
authors.affiliation: Cellular and Molecular Neuroscience Division, National Brain Research Centre, Nainwal Mode, Manesar, Gurgaon, Haryana 122051, India.
authors.forename: R
authors.initials: R
authors.lastname: Ghildiyal
authors.affiliation: Cellular and Molecular Neuroscience Division, National Brain Research Centre, Nainwal Mode, Manesar, Gurgaon, Haryana 122051, India.
authors.forename: N P
authors.initials: NP
authors.lastname: Anto
authors.affiliation: Cellular and Molecular Neuroscience Division, National Brain Research Centre, Nainwal Mode, Manesar, Gurgaon, Haryana 122051, India.
authors.forename: E
authors.initials: E
authors.lastname: Sen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011770:Pyruvate Kinase / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D010879:Piperazines; D017382:Reactive Oxygen Species; C000606460:TP73 protein, human; D014157:Transcription Factors; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C002511:chaetocin; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D050880:p300-CBP Transcription Factors; D006593:Hexokinase; D011770:Pyruvate Kinase; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose