N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer.
N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer.
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N6-甲基腺苷读取器 IMP2 稳定 ZFAS1/OLA1 轴并激活 Warburg 效应：对结直肠癌的影响
DOI：
10.1186/s13045-021-01204-0
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发表时间：
2021-11-07
影响因子：
28.5
通讯作者：
Wei M
中科院分区：
文献类型：
--
作者：
Lu S;Han L;Hu X;Sun T;Xu D;Li Y;Chen Q;Yao W;He M;Wang Z;Wu H;Wei M
越来越多的证据表明，N6-甲基腺嘌呤（m6 A）调节剂有助于结直肠癌（CRC）的病因和进展。然而，m6 A阅读器参与糖酵解代谢的确切机制仍不清楚。本文旨在用糖酵解代谢来干扰m6 A阅读器，并揭示CRC进展的新机制。通过生物信息学、ISH和IHC分析候选lncRNA与m6 A reader的关系。采用MTT、CFA、trans-well、细胞凋亡、western blot、qRT-PCR和异种移植小鼠模型等体内、体外实验研究这些指标的生物学功能。采用乳酸检测、ATP活性检测和ECAR分析来验证下游靶标的生物学功能。利用生物信息学、RNA稳定性、RIP实验和RNA pull-down分析等方法探讨其分子机制。我们发现，m6 A阅读器IMP 2与长非编码RNA（lncRNA）ZFAS 1以m6 A调节依赖性方式发生串扰，随后在CRC增殖和进展期间增加了Obg样ATP酶1（OLA 1）和三磷酸腺苷（ATP）水解和糖酵解的募集。具体而言，在CRC细胞和配对CRC群组中，IMP 2和ZFAS 1显著过表达，m6 A水平升高（n = 144）。这些指标可作为预测结直肠癌预后的独立生物标志物。值得注意的是，IMP 2调节ZFAS 1表达，并增强CRC细胞增殖，集落形成和凋亡抑制;因此，它是致癌的。在机制上，ZFAS 1在RGGAC/RRACH元件内的腺苷+843处以m6 A依赖性方式被修饰。因此，IMP 2的KH 3 -4结构域与ZFAS 1之间的直接相互作用（其中IMP 2充当m6 A修饰的ZFAS 1的阅读器并促进ZFAS 1的RNA稳定性）对于CRC的发展至关重要。更重要的是，稳定化的ZFAS 1识别OLA 1的OBG型功能结构域，其促进ATP结合位点的暴露（NVGKST，32-37），增强其蛋白质活性，并最终加速ATP水解和瓦尔堡效应。我们的研究结果揭示了一种新的促癌机制，即m6 A阅读器稳定lncRNA的关键调节网络，它们共同促进CRC发病机制中的线粒体能量代谢。在线版本包含补充材料，可通过10.1186/s13045-021-01204-0获得。
Accumulating evidence shows that N6-methyladenine (m6A) modulators contribute to the etiology and progression of colorectal cancer (CRC). However, the exact mechanisms of m6A reader involved in glycolytic metabolism remain vague. This article aimed to crosstalk the m6A reader with glycolytic metabolism and reveal a new mechanism for the progression of CRC. The relationship between candidate lncRNA and m6A reader was analyzed by bioinformatics, ISH and IHC assays. In vivo and in vitro studies (including MTT, CFA, trans-well, apoptosis, western blot, qRT-PCR and xenograft mouse models) were utilized to explore the biological functions of these indicators. Lactate detection, ATP activity detection and ECAR assays were used to verify the biological function of the downstream target. The bioinformatics, RNA stability, RIP experiments and RNA pull-down assays were used to explore the potential molecular mechanisms. We identified that the crosstalk of the m6A reader IMP2 with long-noncoding RNA (lncRNA) ZFAS1 in an m6A modulation-dependent manner, subsequently augmented the recruitment of Obg-like ATPase 1 (OLA1) and adenosine triphosphate (ATP) hydrolysis and glycolysis during CRC proliferation and progression. Specifically, IMP2 and ZFAS1 are significantly overexpressed with elevated m6A levels in CRC cells and paired CRC cohorts (n = 144). These indicators could be independent biomarkers for CRC prognostic prediction. Notably, IMP2 regulated ZFAS1 expression and enhanced CRC cell proliferation, colony formation, and apoptosis inhibition; thus, it was oncogenic. Mechanistically, ZFAS1 is modified at adenosine +843 within the RGGAC/RRACH element in an m6A-dependent manner. Thus, direct interaction between the KH3–4 domain of IMP2 and ZFAS1 where IMP2 serves as a reader for m6A-modified ZFAS1 and promotes the RNA stability of ZFAS1 is critical for CRC development. More importantly, stabilized ZFAS1 recognizes the OBG-type functional domain of OLA1, which facilitated the exposure of ATP-binding sites (NVGKST, 32–37), enhanced its protein activity, and ultimately accelerated ATP hydrolysis and the Warburg effect. Our findings reveal a new cancer-promoting mechanism, that is, the critical modulation network underlying m6A readers stabilizes lncRNAs, and they jointly promote mitochondrial energy metabolism in the pathogenesis of CRC. The online version contains supplementary material available at 10.1186/s13045-021-01204-0.
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影响因子：
64.5
作者：
Hafner M;Landthaler M;Burger L;Khorshid M;Hausser J;Berninger P;Rothballer A;Ascano M Jr;Jungkamp AC;Munschauer M;Ulrich A;Wardle GS;Dewell S;Zavolan M;Tuschl T
通讯作者：
Tuschl T
影响因子：
3.8
作者：
Pasiliao CC;Chang CW;Sutherland BW;Valdez SM;Schaeffer D;Yapp DT;Ng SS
通讯作者：
Ng SS
R-2-hydroxyglutarate 通过靶向 FTO/m(6)A/PFKP/LDHB 轴，抑制白血病中的有氧糖酵解。
影响因子：
16
作者：
Qing Y;Dong L;Gao L;Li C;Li Y;Han L;Prince E;Tan B;Deng X;Wetzel C;Shen C;Gao M;Chen Z;Li W;Zhang B;Braas D;Ten Hoeve J;Sanchez GJ;Chen H;Chan LN;Chen CW;Ann D;Jiang L;Müschen M;Marcucci G;Plas DR;Li Z;Su R;Chen J
通讯作者：
Chen J
影响因子：
5.6
作者：
Dahlem, Charlotte;Barghash, Ahmad;Kessler, Sonja M.
通讯作者：
Kessler, Sonja M.
m6A 依赖性糖酵解促进结直肠癌进展
影响因子：
37.3
作者：
Shen, Chaoqin;Xuan, Baoqin;Hong, Jie
通讯作者：
Hong, Jie