کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1983297 1539865 2016 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
G9a inhibition induced PKM2 regulates autophagic responses
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
G9a inhibition induced PKM2 regulates autophagic responses
چکیده انگلیسی


• Pharmacological and siRNA mediated G9a inhibition induces LC3B expression in glioma cells.
• G9a inhibition induced Akt-HIF-1α axis increases PKM2 levels and decreases YAP1 phosphorylation.
• Phosphorylation of YAP1 is PKM2 dependent manner.
• LC3B induction upon G9a inhibition is abrogated upon PKM2 knock-down and YAP1 over-expression.
• Pharmacological inhibition of G9a does not affect tumor growth in vivo but induces LC3B expression.

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The International Journal of Biochemistry & Cell Biology - Volume 78, September 2016, Pages 87–95
نویسندگان
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