A feedback circuit comprising EHD1 and 14-3-3ζ sustains β-catenin/c-Myc-mediated aerobic glycolysis and proliferation in non-small cell lung cancer. (1st November 2021)

• Record Type: Journal Article
• Authors: Huang, Jian; Tian, Fanglin; Song, Ying; Cao, Mengru; Yan, Shi; Lan, Xiuwen; Cui, Yimeng; Cui, Yaowen; Cui, Yue; Jia, Dexin; Cai, Li; Xing, Ying; Wang, Xin
• Is Part Of: Cancer letters. Volume 520(2021)
• Page Start: 12
• Page End: 25
• Publication Date: 2021-11-01
• Subjects: EHD1 -- Metabolic reprogramming -- Tumor proliferation -- Positive feedback loop; CCK-8 Cell Counting Kit-8 -- CCND1 Cyclin D1 -- ChIP Chromatin immunoprecipitation -- ChIP-seq Chromatin immunoprecipitation-sequencing -- Co-IP Coimmunoprecipitation -- ECAR Extracellular acidification rate -- EGFR-TKI Epidermal growth factor receptor-tyrosine kinase inhibitor -- EHD1 Mammalian Eps15 homology domain 1 -- EMT Epithelial-mesenchymal transition -- ENCODE The Encyclopedia of DNA Elements -- ENO1 Enolase 1 -- ERC Endocytic recycling compartment -- HK2 Hexokinase 2 -- IF Immunofluorescence -- IHC Immunohistochemical -- KEGG Kyoto Encyclopedia of Genes and Genomes -- LDHA Lactate dehydrogenase A -- LUNX Lung-specific X -- NSCLC Non-small cell lung cancer -- OD Optical density -- OS Overall survival -- PDK1 Pyruvate dehydrogenase kinase 1 -- PFKL Phosphofructokinase-1, liver type -- PGK1 Phosphoglycerate kinase 1 -- qRT-PCR Quantitative real-time PCR -- shRNA Short hairpin RNA -- siRNAs Small interfering RNAs -- SOX2 SRY-box 2 -- SOX9 SRY-box 9 -- SUVmax Maximum standard uptake value -- TCF/LEF T cell factor/lymphoid enhancer factor -- TCGA The Cancer Genome Atlas -- TNKS Tankyrase; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.06.023
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Mammalian Eps15 homology domain 1 (EHD1) participates in the development of non-small cell lung cancer (NSCLC). However, its role in mediating aerobic glycolysis remains unclear. Herein, microarray analysis revealed that EHD1 expression was significantly correlated with the glycolysis/gluconeogenesis pathway. Clinically, EHD1 expression was positively correlated with the maximum standard uptake value (SUVmax) in 18 F-FDG PET/CT scans. Additionally, EHD1 knockdown inhibited aerobic glycolysis and proliferation in vitro and in vivo. Furthermore, Wnt/β-catenin signaling was identified as a critical EHD1-regulated pathway. Co-IP, native gel electrophoresis, and immunoblotting showed that EHD1 contributed to 14-3-3 dimerization via 14-3-3ζ and subsequent activation of β-catenin/c-Myc signaling. Analysis of the EHD1 regulatory region via ENCODE revealed the potential for c-Myc recruitment, leading to transcriptional activation of EHD1 and formation of an EHD1/14-3-3ζ/β-catenin/c-Myc positive feedback circuit. Notably, blocking this circuit with a Wnt/β-catenin inhibitor dramatically inhibited tumor growth in vivo. The positive correlations among EHD1, 14-3-3ζ, c-Myc, and LDHA were further confirmed in NSCLC tissues. Collectively, our study demonstrated that EHD1 activates a 14-3-3ζ/β-catenin/c-Myc regulatory circuit that synergistically promotes aerobic glycolysis and may constitute a promising therapeutic target for NSCLC. Highlights: High EHD1 levels correlate with aerobic glycolysis and NSCLC proliferation in vitro and in vivo. EHD1 modulates 14-3-3 dimerization via 14-3-3ζ, thereby activating 14-3-3ζ/β-catenin/c-Myc signaling. c-Myc-mediated transcriptional activation of EHD1 modulates aerobic glycolysis via forming a positive feedback circuit. EHD1 overexpression and increased 14-3-3ζ, c-Myc levels predict unfavorable prognosis in clinical NSCLC specimens. Blocking the EHD1/14-3-3ζ/β-catenin/c-Myc circuit constitutes a potential treatment strategy for patients with NSCLC.