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

• 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
• Journal Title: JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
• Volume: Volume 42, Number 1
• Publisher: BMC | 2023-01-02, Pages 1-1
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/s13046-022-02574-0
• Subjects: Health Sciences, Pharmacy; Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; ENO2; PKM2; HNSCC; Glucose metabolism; Cell cycle; AP-III-a4; SQUAMOUS-CELL CARCINOMA; PYRUVATE-KINASE M2; PKM2 PROMOTES; BETA-CATENIN; METABOLISM; ENOLASE; TRANSACTIVATION; PROLIFERATION; ACTIVATION; INHIBITOR

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.