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Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development
BACKGROUND: Enolase 2 (ENO2) is a crucial glycolytic enzyme in cancer metabolic process and acts as a “moonlighting” protein to play various functions in diverse cellular processes unrelated to glycolysis. ENO2 is highly expressed in head and neck squamous cell carcinoma (HNSCC) tissues relative to...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9806895/ https://www.ncbi.nlm.nih.gov/pubmed/36588153 http://dx.doi.org/10.1186/s13046-022-02574-0 |
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author | Gao, Lixia Yang, Fan Tang, Dianyong Xu, Zhigang Tang, Yan Yang, Donglin Sun, Deping Chen, Zhongzhu Teng, Yong |
author_facet | Gao, Lixia Yang, Fan Tang, Dianyong Xu, Zhigang Tang, Yan Yang, Donglin Sun, Deping Chen, Zhongzhu Teng, Yong |
author_sort | Gao, Lixia |
collection | PubMed |
description | BACKGROUND: Enolase 2 (ENO2) is a crucial glycolytic enzyme in cancer metabolic process and acts as a “moonlighting” protein to play various functions in diverse cellular processes unrelated to glycolysis. ENO2 is highly expressed in head and neck squamous cell carcinoma (HNSCC) tissues relative to normal tissues; however, its impact and underlying regulatory mechanisms in HNSCC malignancy remain unclear. METHODS: Molecular alterations were examined by bioinformatics, qRT-PCR, western blotting, immunofluorescence, immunohistochemistry, immunoprecipitation, and ChIP-PCR assays. Metabolic changes were assessed by intracellular levels of ATP and glucose. Animal study was used to evaluate the therapeutic efficacy of the ENO inhibitor. RESULTS: ENO2 is required for HNSCC cell proliferation and glycolysis, which, surprisingly, is partially achieved by controlling PKM2 protein stability and its nuclear translocation. Mechanistically, loss of ENO2 expression promotes PKM2 protein degradation via the ubiquitin-proteasome pathway and prevents the switch of cytoplasmic PKM2 to the nucleus by inactivating AKT signaling, leading to a blockade in PKM2-mediated glycolytic flux and CCND1-associated cell cycle progression. In addition, treatment with the ENO inhibitor AP-III-a4 significantly induces HNSCC remission in a preclinical mouse model. CONCLUSION: Our work elucidates the signaling basis underlying ENO2-dependent HNSCC development, providing evidence to establish a novel ENO2-targeted therapy for treating HNSCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02574-0. |
format | Online Article Text |
id | pubmed-9806895 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-98068952023-01-03 Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development Gao, Lixia Yang, Fan Tang, Dianyong Xu, Zhigang Tang, Yan Yang, Donglin Sun, Deping Chen, Zhongzhu Teng, Yong J Exp Clin Cancer Res Research BACKGROUND: Enolase 2 (ENO2) is a crucial glycolytic enzyme in cancer metabolic process and acts as a “moonlighting” protein to play various functions in diverse cellular processes unrelated to glycolysis. ENO2 is highly expressed in head and neck squamous cell carcinoma (HNSCC) tissues relative to normal tissues; however, its impact and underlying regulatory mechanisms in HNSCC malignancy remain unclear. METHODS: Molecular alterations were examined by bioinformatics, qRT-PCR, western blotting, immunofluorescence, immunohistochemistry, immunoprecipitation, and ChIP-PCR assays. Metabolic changes were assessed by intracellular levels of ATP and glucose. Animal study was used to evaluate the therapeutic efficacy of the ENO inhibitor. RESULTS: ENO2 is required for HNSCC cell proliferation and glycolysis, which, surprisingly, is partially achieved by controlling PKM2 protein stability and its nuclear translocation. Mechanistically, loss of ENO2 expression promotes PKM2 protein degradation via the ubiquitin-proteasome pathway and prevents the switch of cytoplasmic PKM2 to the nucleus by inactivating AKT signaling, leading to a blockade in PKM2-mediated glycolytic flux and CCND1-associated cell cycle progression. In addition, treatment with the ENO inhibitor AP-III-a4 significantly induces HNSCC remission in a preclinical mouse model. CONCLUSION: Our work elucidates the signaling basis underlying ENO2-dependent HNSCC development, providing evidence to establish a novel ENO2-targeted therapy for treating HNSCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02574-0. BioMed Central 2023-01-02 /pmc/articles/PMC9806895/ /pubmed/36588153 http://dx.doi.org/10.1186/s13046-022-02574-0 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 Gao, Lixia Yang, Fan Tang, Dianyong Xu, Zhigang Tang, Yan Yang, Donglin Sun, Deping Chen, Zhongzhu Teng, Yong Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development |
title | Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development |
title_full | Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development |
title_fullStr | Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development |
title_full_unstemmed | Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development |
title_short | Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development |
title_sort | mediation of pkm2-dependent glycolytic and non-glycolytic pathways by eno2 in head and neck cancer development |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9806895/ https://www.ncbi.nlm.nih.gov/pubmed/36588153 http://dx.doi.org/10.1186/s13046-022-02574-0 |
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