Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

• Type of Material: Article
• Authors: Lixia Gao, Chongqing University of Arts & Sciences; Fan Yang, Emory University; Dianyong Tang, Chongqing University of Arts & Sciences; Zhigang Xu, Chongqing University of Arts & Sciences; Yan Tang, Chongqing University of Arts & Sciences; Donglin Yang, Chongqing University of Arts & Sciences; Deping Sun, Chongqing Medical University; Zhonghu Chen, Chongqing University of Arts & Sciences; Yong Teng, Emory University
• Language: English
• Date: 2023-01-02
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13046-022-02574-0
• Title of Journal or Parent Work: JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
• Volume: 42
• Issue: 1
• Start Page: 1
• End Page: 1
• Grant/Funding Information: This work was also supported in part by Winship Invest$ Team Science Award (to YT).; This work was supported by the grant funded by the National Natural Science Foundation of China 82203593 (to LG), the Natural Science Foundation Project of Chongqing cstc2021jcyj-bsh0239 (to LG), the Science and Technology Research Program of Chongqing Municipal Education Commission KJQN202101326 (to LG).
• Keywords: PYRUVATE-KINASE M2; Oncology; PKM2; SQUAMOUS-CELL CARCINOMA; ENOLASE; METABOLISM; HNSCC; ACTIVATION; TRANSACTIVATION; Glucose metabolism; Cell cycle; PKM2 PROMOTES; Life Sciences & Biomedicine; AP-III-a4; INHIBITOR; Science & Technology; ENO2; BETA-CATENIN; PROLIFERATION
• Research Categories: Health Sciences, Pharmacy; Health Sciences, Oncology

Abstract

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.