The essential roles of m(6)A RNA modification to stimulate ENO1-dependent glycolysis and tumorigenesis in lung adenocarcinoma.
The essential roles of m(6)A RNA modification to stimulate ENO1-dependent glycolysis and tumorigenesis in lung adenocarcinoma.
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m6A RNA 修饰刺激 ENO1 依赖性糖酵解和肺腺癌肿瘤发生的重要作用
DOI：
10.1186/s13046-021-02200-5
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发表时间：
2022-01-25
期刊：
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Ma L;Xue X;Zhang X;Yu K;Xu X;Tian X;Miao Y;Meng F;Liu X;Guo S;Qiu S;Wang Y;Cui J;Guo W;Li Y;Xia J;Yu Y;Wang J
肺腺癌（LUAD）是肺癌最常见的亚型。患者预后差，现有的LUAD治疗策略远不能令人满意。最近，靶向N6-甲基腺苷（m6 A）修饰的RNA已被认为是一种潜在的策略，以阻止肿瘤的进展。然而，m6 A修饰在LUAD肿瘤发生中的作用尚不清楚。在人LUAD、小鼠模型和细胞系中，通过RNA甲基化测定、斑点印迹、免疫印迹、免疫组织化学和ELISA来评估总体m6 A水平和m6 A写入器、擦除器和读取器的表达。进行细胞活力、3D球体生成、体内LUAD形成、细胞和患者来源的异种移植小鼠中的实验以及存活分析以探索m6 A对LUAD的影响。在研究m6 A如何刺激肿瘤发生的潜在机制中，探索了RNA-蛋白质相互作用、翻译、推定的m6 A位点和糖酵解。大多数人LUAD标本中总体m6 A水平的升高是由m6 A写入甲基转移酶3（胃L3）的上调和擦除alkB同源物5（ALKBH 5）的下调共同引起的。总体m6 A水平升高与LUAD患者的总体生存率差相关。通过敲除胃L3和过表达ALKBH 5来降低m6 A水平抑制了LUAD细胞中3D球状体的生成和小鼠肺内肿瘤的形成。从机制上讲，糖酵解和肿瘤发生的m6 A依赖性刺激通过烯醇化酶1（ENO 1）发生。ENO 1 mRNA在359 A处被m6 A甲基化，这促进了它与m6 A阅读器YTH N6-甲基腺苷RNA结合蛋白1（YTHDF 1）的结合，并导致增强的ENO 1翻译。在人LUAD中，ENO 1与胃L3和总体m6 A水平呈正相关，与ALKBH 5呈负相关。此外，m6 A依赖性的ENO 1升高与LUAD进展相关。在临床前模型中，具有较高总体m6 A水平的肿瘤对LUAD中的泛甲基化、糖酵解和ENO活性的抑制表现出更敏感的反应。LUAD中糖酵解和肿瘤发生的m6 A依赖性刺激至少部分由胃L3的上调、ALKBH 5的下调和YTHDF 1介导的ENO 1翻译的刺激协调。阻断这种机制可能是m6 A依赖性LUAD的潜在治疗策略。在线版本包含补充材料，可通过10.1186/s13046-021-02200-5获得。
Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Patient prognosis is poor, and the existing therapeutic strategies for LUAD are far from satisfactory. Recently, targeting N6-methyladenosine (m6A) modification of RNA has been suggested as a potential strategy to impede tumor progression. However, the roles of m6A modification in LUAD tumorigenesis is unknown. Global m6A levels and expressions of m6A writers, erasers and readers were evaluated by RNA methylation assay, dot blot, immunoblotting, immunohistochemistry and ELISA in human LUAD, mouse models and cell lines. Cell viability, 3D-spheroid generation, in vivo LUAD formation, experiments in cell- and patient-derived xenograft mice and survival analysis were conducted to explore the impact of m6A on LUAD. The RNA-protein interactions, translation, putative m6A sites and glycolysis were explored in the investigation of the mechanism underlying how m6A stimulates tumorigenesis. The elevation of global m6A level in most human LUAD specimens resulted from the combined upregulation of m6A writer methyltransferase 3 (METTL3) and downregulation of eraser alkB homolog 5 (ALKBH5). Elevated global m6A level was associated with a poor overall survival in LUAD patients. Reducing m6A levels by knocking out METTL3 and overexpressing ALKBH5 suppressed 3D-spheroid generation in LUAD cells and intra-pulmonary tumor formation in mice. Mechanistically, m6A-dependent stimulation of glycolysis and tumorigenesis occurred via enolase 1 (ENO1). ENO1 mRNA was m6A methylated at 359 A, which facilitated it’s binding with the m6A reader YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) and resulted in enhanced translation of ENO1. ENO1 positively correlated with METTL3 and global m6A levels, and negatively correlated with ALKBH5 in human LUAD. In addition, m6A-dependent elevation of ENO1 was associated with LUAD progression. In preclinical models, tumors with a higher global m6A level showed a more sensitive response to the inhibition of pan-methylation, glycolysis and ENO activity in LUAD. The m6A-dependent stimulation of glycolysis and tumorigenesis in LUAD is at least partially orchestrated by the upregulation of METTL3, downregulation of ALKBH5, and stimulation of YTHDF1-mediated ENO1 translation. Blocking this mechanism may represent a potential treatment strategy for m6A-dependent LUAD. The online version contains supplementary material available at 10.1186/s13046-021-02200-5.
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影响因子：
16.6
作者：
Kan L;Grozhik AV;Vedanayagam J;Patil DP;Pang N;Lim KS;Huang YC;Joseph B;Lin CJ;Despic V;Guo J;Yan D;Kondo S;Deng WM;Dedon PC;Jaffrey SR;Lai EC
通讯作者：
Lai EC
RNA m6A 阅读器 YTHDF2 通过靶向 AXIN1/Wnt/β-catenin 信号传导促进肺腺癌细胞增殖和转移
影响因子：
9
作者：
Li Y;Sheng H;Ma F;Wu Q;Huang J;Chen Q;Sheng L;Zhu X;Zhu X;Xu M
通讯作者：
Xu M
影响因子：
64.5
作者：
Jin, Chengcheng;Lagoudas, Georgia K.;Jacks, Tyler
通讯作者：
Jacks, Tyler
影响因子：
6
作者：
Choi J;Kim H;Kim Y;Jang M;Jeon J;Hwang YI;Shon WJ;Song YW;Kang JS;Lee WJ
通讯作者：
Lee WJ
影响因子：
14.8
作者：
Leonard PG;Satani N;Maxwell D;Lin YH;Hammoudi N;Peng Z;Pisaneschi F;Link TM;Lee GR 4th;Sun D;Prasad BAB;Di Francesco ME;Czako B;Asara JM;Wang YA;Bornmann W;DePinho RA;Muller FL
通讯作者：
Muller FL