Aerobic glycolysis is critical for tumor growth and metastasis.Previously,we have found that the overexpression of the inhibitor of growth 5(ING5)inhibits lung cancer aggressiveness and epithelial–mesenchymal transit...Aerobic glycolysis is critical for tumor growth and metastasis.Previously,we have found that the overexpression of the inhibitor of growth 5(ING5)inhibits lung cancer aggressiveness and epithelial–mesenchymal transition(EMT).However,whether ING5 regulates lung cancer metabolism reprogramming remains unknown.Here,by quantitative proteomics,we showed that ING5 differentially regulates protein phosphorylation and identified a new site(Y163)of the key glycolytic enzyme PDK1 whose phosphorylation was upregulated 13.847-fold.By clinical study,decreased p-PDK1Y163 was observed in lung cancer tissues and correlated with poor survival.p-PDK1Y163 represents the negative regulatory mechanism of PDK1 by causing PDHA1 dephosphorylation and activation,leading to switching from glycolysis to oxidative phosphorylation,with increasing oxygen consumption and decreasing lactate production.These effects could be impaired by PDK1Y163F mutation,which also impaired the inhibitory effects of ING5 on cancer cell EMT and invasiveness.Mouse xenograft models confirmed the indispensable role of p-PDK1Y163 in ING5-inhibited tumor growth and metastasis.By siRNA screening,ING5-upregulated TIE1 was identified as the upstream tyrosine protein kinase targeting PDK1Y163.TIE1 knockdown induced the dephosphorylation of PDK1Y163 and increased the migration and invasion of lung cancer cells.Collectively,ING5 overexpression—upregulated TIE1 phosphorylates PDK1Y163,which is critical for the inhibition of aerobic glycolysis and invasiveness of lung cancer cells.展开更多
目的:探讨METTL3在非小细胞肺癌中的表达及作用,并探讨其可能的机制。方法:通过慢病毒转染,在HCC827细胞中过表达和敲除METTL3,并通过免疫印迹验证METTL3蛋白表达。免疫印迹检测HCC827细胞中生长抑制物家族成5(Methyltransferase Like 3...目的:探讨METTL3在非小细胞肺癌中的表达及作用,并探讨其可能的机制。方法:通过慢病毒转染,在HCC827细胞中过表达和敲除METTL3,并通过免疫印迹验证METTL3蛋白表达。免疫印迹检测HCC827细胞中生长抑制物家族成5(Methyltransferase Like 3,甲基转移酶3)调控ING5(Inhibitor Of Growth Family Member 5,METTL3)。使用基因表达交互分析(Gene Expression Profiling Interactive Analysis,GEPIA)探究了METTL3和ING5在非小细胞肺癌组织和正常组织中的表达相关性。用CCK-8法检测METTL3和ING5表达对非小细胞肺癌细胞增殖的影响。使用KM-plotter验证METTL3、ING5的表达与非小细胞肺癌的总生存期(OS)、进展后生存期(PPS)和无进展生存期(PFS)之间的相关性。结果:免疫印迹结果显示,在HCC827细胞中METTL3过表达上调了ING5蛋白的表达,而METTL3表达下调了ING5蛋白的表达。GEPIA数据库分析显示METTL3在非小细胞肺癌中的表达明显低于正常组织(P<0.05)。CCK-8检测结果显示,与对照组相比METTL3缺失促进了HCC827细胞的增殖能力,而METTL3过表达显著抑制了HCC827细胞的增殖能力。此外,METTL3通过ING5调控非小细胞肺癌细胞的增殖能力。KM-plotter分析显示METTL3、ING5 m RNA的表达与非小细胞肺癌患者的生存有较好的预后关系。结论:METTL3在非小细胞肺癌低表达,并通过调控ING5的表达在非小细胞肺癌的发生进展中发挥重要地抑癌基因作用。展开更多
肿瘤的发生是个涉及多基因改变的复杂过程,其中癌基因的激活和抑癌基因的失活是两大关键要素.生长抑制因子（inhibitor of growth,ING）作为候选抑癌基因家族,在肿瘤的发生、发展中起到重要的抑制作用.ING5是最新发现的生长抑制因子家...肿瘤的发生是个涉及多基因改变的复杂过程,其中癌基因的激活和抑癌基因的失活是两大关键要素.生长抑制因子（inhibitor of growth,ING）作为候选抑癌基因家族,在肿瘤的发生、发展中起到重要的抑制作用.ING5是最新发现的生长抑制因子家族成员,研究结果表明ING5与P53相互作用并促进P53转录活化,从而引起细胞周期阻滞和凋亡.同时ING5是两种组蛋白乙酰基转移酶复合体的本结构,参与染色质重构的过程.它作为组蛋白和组蛋白乙酰基转移酶（histone acetyltransferase,HAT）之间的桥梁分子,可能通过调控基因的表达而发挥抑癌作用.文章将对ING5的抑癌作用机制作一综述.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81672269,81272587,and 81172223).
文摘Aerobic glycolysis is critical for tumor growth and metastasis.Previously,we have found that the overexpression of the inhibitor of growth 5(ING5)inhibits lung cancer aggressiveness and epithelial–mesenchymal transition(EMT).However,whether ING5 regulates lung cancer metabolism reprogramming remains unknown.Here,by quantitative proteomics,we showed that ING5 differentially regulates protein phosphorylation and identified a new site(Y163)of the key glycolytic enzyme PDK1 whose phosphorylation was upregulated 13.847-fold.By clinical study,decreased p-PDK1Y163 was observed in lung cancer tissues and correlated with poor survival.p-PDK1Y163 represents the negative regulatory mechanism of PDK1 by causing PDHA1 dephosphorylation and activation,leading to switching from glycolysis to oxidative phosphorylation,with increasing oxygen consumption and decreasing lactate production.These effects could be impaired by PDK1Y163F mutation,which also impaired the inhibitory effects of ING5 on cancer cell EMT and invasiveness.Mouse xenograft models confirmed the indispensable role of p-PDK1Y163 in ING5-inhibited tumor growth and metastasis.By siRNA screening,ING5-upregulated TIE1 was identified as the upstream tyrosine protein kinase targeting PDK1Y163.TIE1 knockdown induced the dephosphorylation of PDK1Y163 and increased the migration and invasion of lung cancer cells.Collectively,ING5 overexpression—upregulated TIE1 phosphorylates PDK1Y163,which is critical for the inhibition of aerobic glycolysis and invasiveness of lung cancer cells.
文摘目的:探讨METTL3在非小细胞肺癌中的表达及作用,并探讨其可能的机制。方法:通过慢病毒转染,在HCC827细胞中过表达和敲除METTL3,并通过免疫印迹验证METTL3蛋白表达。免疫印迹检测HCC827细胞中生长抑制物家族成5(Methyltransferase Like 3,甲基转移酶3)调控ING5(Inhibitor Of Growth Family Member 5,METTL3)。使用基因表达交互分析(Gene Expression Profiling Interactive Analysis,GEPIA)探究了METTL3和ING5在非小细胞肺癌组织和正常组织中的表达相关性。用CCK-8法检测METTL3和ING5表达对非小细胞肺癌细胞增殖的影响。使用KM-plotter验证METTL3、ING5的表达与非小细胞肺癌的总生存期(OS)、进展后生存期(PPS)和无进展生存期(PFS)之间的相关性。结果:免疫印迹结果显示,在HCC827细胞中METTL3过表达上调了ING5蛋白的表达,而METTL3表达下调了ING5蛋白的表达。GEPIA数据库分析显示METTL3在非小细胞肺癌中的表达明显低于正常组织(P<0.05)。CCK-8检测结果显示,与对照组相比METTL3缺失促进了HCC827细胞的增殖能力,而METTL3过表达显著抑制了HCC827细胞的增殖能力。此外,METTL3通过ING5调控非小细胞肺癌细胞的增殖能力。KM-plotter分析显示METTL3、ING5 m RNA的表达与非小细胞肺癌患者的生存有较好的预后关系。结论:METTL3在非小细胞肺癌低表达,并通过调控ING5的表达在非小细胞肺癌的发生进展中发挥重要地抑癌基因作用。
文摘肿瘤的发生是个涉及多基因改变的复杂过程,其中癌基因的激活和抑癌基因的失活是两大关键要素.生长抑制因子（inhibitor of growth,ING）作为候选抑癌基因家族,在肿瘤的发生、发展中起到重要的抑制作用.ING5是最新发现的生长抑制因子家族成员,研究结果表明ING5与P53相互作用并促进P53转录活化,从而引起细胞周期阻滞和凋亡.同时ING5是两种组蛋白乙酰基转移酶复合体的本结构,参与染色质重构的过程.它作为组蛋白和组蛋白乙酰基转移酶（histone acetyltransferase,HAT）之间的桥梁分子,可能通过调控基因的表达而发挥抑癌作用.文章将对ING5的抑癌作用机制作一综述.
