title: G9a inhibition induced PKM2 regulates autophagic responses.
abstract: Epigenetic regulation by histone methyltransferase G9a is known to control autophagic responses. As the link between autophagy and metabolic homeostasis is widely accepted, we investigated whether G9a affects metabolic circuitries to affect autophagic response in glioma cells. Both pharmacological inhibition and siRNA mediated knockdown of G9a increased autophagy marker LC3B in glioma cells. G9a inhibitor BIX-01294 (BIX) induced Akt-dependent increase in HIF-1α expression and activity. Inhibition of Akt-HIF-1α axis reversed BIX-mediated (i) increase in LC3B expression and (ii) decrease in Yes-associated protein 1 (YAP1) phosphorylation. YAP1 over-expression abrogated BIX induced increase in LC3B expression. Interestingly, BIX induced increase in metabolic modelers TIGAR (TP53-induced glycolysis and apoptosis regulator) and PKM2 (Pyruvate kinase M2) were crucial for BIX-mediated changes, as transfection with TIGAR mutant or PKM2 siRNA reversed BIX-mediated alterations in pYAP1 and LC3B expression. Coherent with the in vitro observation, BIX had no significant effect on the tumor burden in heterotypic xenograft glioma mouse model. Elevated LC3B and PKM2 in BIX-treated xenograft tissue was accompanied by decreased YAP1 levels. Taken together, our findings suggest that Akt-HIF-1α axis driven PKM2-YAP1 cross talk activates autophagic responses in glioma cells upon G9a inhibition.
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India.
authors.forename: Fahim
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India.
authors.forename: Deobrat
authors.initials: D
authors.lastname: Dixit
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India.
authors.forename: Shanker Datt
authors.initials: SD
authors.lastname: Joshi
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India. Electronic address: ellora@nbrc.ac.in.
authors.forename: Ellora
authors.initials: E
authors.lastname: Sen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006649:Histocompatibility Antigens / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D013963:Thyroid Hormones / Q000378:metabolism*; D014157:Transcription Factors; D000072160:Tumor Protein p73 / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001381:Azepines; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D006649:Histocompatibility Antigens; D011495:Histone-Lysine N-Methyltransferase; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D011799:Quinazolines; D013963:Thyroid Hormones; D014157:Transcription Factors; D000072160:Tumor Protein p73; D000091102:YAP-Signaling Proteins; D000097810:Thyroid Hormone-Binding Proteins; C518299:BIX 01294; C497442:HIF1A protein, human; C502070:MAP1LC3B protein, human; C088374:YAP1 protein, human; C445405:EHMT2 protein, human
keywords: Autophagy; G9a; LC3B; PKM2