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MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation

BACKGROUND: 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 prec...

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Autores principales: Wu, Yang, Wang, Yichun, Yao, Hanhui, Li, Heng, Meng, Fanzheng, Li, Qidong, Lin, Xiansheng, Liu, Lianxin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9727912/
https://www.ncbi.nlm.nih.gov/pubmed/36476366
http://dx.doi.org/10.1186/s13046-022-02547-3
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author Wu, Yang
Wang, Yichun
Yao, Hanhui
Li, Heng
Meng, Fanzheng
Li, Qidong
Lin, Xiansheng
Liu, Lianxin
author_facet Wu, Yang
Wang, Yichun
Yao, Hanhui
Li, Heng
Meng, Fanzheng
Li, Qidong
Lin, Xiansheng
Liu, Lianxin
author_sort Wu, Yang
collection PubMed
description BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02547-3.
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spelling pubmed-97279122022-12-08 MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation Wu, Yang Wang, Yichun Yao, Hanhui Li, Heng Meng, Fanzheng Li, Qidong Lin, Xiansheng Liu, Lianxin J Exp Clin Cancer Res Research BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02547-3. BioMed Central 2022-12-07 /pmc/articles/PMC9727912/ /pubmed/36476366 http://dx.doi.org/10.1186/s13046-022-02547-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wu, Yang
Wang, Yichun
Yao, Hanhui
Li, Heng
Meng, Fanzheng
Li, Qidong
Lin, Xiansheng
Liu, Lianxin
MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation
title MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation
title_full MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation
title_fullStr MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation
title_full_unstemmed MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation
title_short MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation
title_sort mnx1-as1, a c-myc induced lncrna, promotes the warburg effect by regulating pkm2 nuclear translocation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9727912/
https://www.ncbi.nlm.nih.gov/pubmed/36476366
http://dx.doi.org/10.1186/s13046-022-02547-3
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