MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation.
MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation.
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DOI：
10.1186/s13046-022-02547-3
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发表时间：
2022-12-07
影响因子：
11.3
通讯作者：
Liu, Lianxin
中科院分区：
文献类型：
--
作者：
Wu, Yang;Wang, Yichun;Yao, Hanhui;Li, Heng;Meng, Fanzheng;Li, Qidong;Lin, Xiansheng;Liu, Lianxin
糖酵解改变是与瓦尔堡效应相关的最基本的代谢变化。一些糖酵解酶，如PKM 2，癌细胞中的主要丙酮酸激酶，已被证明参与有助于肿瘤代谢的非糖酵解功能。然而，确切的机制尚未完全理解。在体外和体内评估MNX 1-AS 1在肝细胞癌进展中的作用。采用北方印迹、RNA pulldown、质谱、RNA结合蛋白免疫沉淀、ChIP、荧光素酶报告基因分析、RNA荧光原位杂交和免疫荧光染色等方法探讨MNX 1-AS 1在肝细胞癌（HCC）中的分子机制。在这里，我们剖析MNX 1-AS 1，一个长的非编码RNA（lncRNA），如何加强瓦尔堡效应，通过促进非糖酵解作用的PKM 2在细胞核中。我们发现，与正常肝细胞相比，MNX 1-AS 1在HCC来源的细胞系和组织中经常过表达，这一发现与其作为泛癌表达lncRNA的状态一致。在HCC的背景下，我们显示MNX 1-AS 1作为支架促进PKM 2和importin α5之间的相互作用。作为对EGFR活化的响应，所产生的三元复合物驱动PKM 2易位到细胞核中。因此，糖酵解途径组分包括瓦尔堡效应的关键介质（LDHA、GLUT 1和PDK 1）通过PKM 2的共激活因子功能上调。操纵MNX 1-AS 1引起了对糖酵解的强烈影响，与体外和异种移植模型中HCC生长的显著变化相关，表明MNX 1-AS 1对致瘤表型的显著贡献。此外，虽然MNX 1-AS 1表达由c-Myc驱动，但其与PKM 2相关的作用显示为下游且独立于c-Myc。鉴于MNX 1-AS 1作为泛癌上调的lncRNA的状态，这隐含地突出了靶向MNX 1-AS 1以在一系列肿瘤类型中选择性地对抗瓦尔堡效应的潜力。在线版本包含补充材料，可通过10.1186/s13046-022-02547-3获得。
Altered glycolysis is the most fundamental metabolic change associated with the Warburg effect. Some glycolytic enzymes such as PKM2, the dominant pyruvate kinase in cancer cells, have been shown to engage in non-glycolytic functions that contribute to tumor metabolism. However, the precise mechanisms are not completely understood. The role of MNX1-AS1 in hepatocellular carcinoma progression was assessed both in vitro and in vivo. Northern blotting, RNA pulldown, mass spectrometry, RNA-binding protein immunoprecipitation, ChIP, luciferase reporter assays, RNA FISH and immunofluorescence staining were used to explore the detail molecular mechanism of MNX1-AS1 in hepatocellular carcinoma (HCC). Here we dissect how MNX1-AS1, a long non-coding RNA (lncRNA), reinforces the Warburg effect through facilitating the non-glycolytic actions of PKM2 in the cell nucleus. We found that MNX1-AS1 expression was frequently overexpressed in HCC-derived cell lines and tissues compared to their normal hepatic cell counterparts, a finding consistent with its status as pan-cancer expressed lncRNA. In the context of HCC, we show MNX1-AS1 acts as a scaffold to promote interactions between PKM2 and importin α5. In response to EGFR activation, the resulting ternary complex drives the translocation of PKM2 into the nucleus. In consequence, glycolytic pathway components including key mediators of the Warburg effect (LDHA, GLUT1 and PDK1) are upregulated though the coactivator function of PKM2. Manipulating MNX1-AS1 elicited robust effects on glycolysis associated with marked changes in HCC growth in vitro and in xenograft models, indicative of the significant contribution of MNX1-AS1 to tumorigenic phenotypes. Moreover, while MNX1-AS1 expression is driven by c-Myc, its actions associated with PKM2 were shown to be downstream and independent of c-Myc. Given the status of MNX1-AS1 as a pan-cancer upregulated lncRNA, this implicitly highlights the potential of targeting MNX1-AS1 to selectively counter the Warburg effect in a range of tumor types. The online version contains supplementary material available at 10.1186/s13046-022-02547-3.
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