ENO1 Promotes Lung Cancer Metastasis via HGFR and WNT Signaling–Driven Epithelial-to-Mesenchymal Transition

Abstract

ENO1 (α-enolase) expression is significantly correlated with reduced survival and poor prognosis in many cancer types, including lung cancer. However, the function of ENO1 in carcinogenesis remains elusive. In this study, we found that high expression of ENO1 is present in metastatic lung cancer cell lines and malignant tumors and is associated with poor overall survival of patients with lung cancer. Knockdown of ENO1 decreased cancer cell proliferation and invasiveness, whereas overexpression of ENO1 enhanced these processes. Moreover, ENO1 expression promoted tumor growth in orthotopic models and enhanced lung tumor metastasis in tail-vein injection models. These effects were mediated by upregulation of mesenchymal markers N-cadherin and vimentin and the epithelial-to-mesenchymal transition regulator SLUG, along with concurrent downregulation of E-cadherin. Mechanistically, ENO1 interacted with hepatocyte growth factor receptor (HGFR) and activated HGFR and Wnt signaling via increased phosphorylation of HGFR and the Wnt coreceptor LRP5/6. Activation of these signaling axes decreased GSK3β activity via Src–PI3K–AKT signaling and inactivation of the β-catenin destruction complex to ultimately upregulate SLUG and β-catenin. In addition, we generated a chimeric anti-ENO1 mAb (chENO1-22) that can decrease cancer cell proliferation and invasion. chENO1-22 attenuated cancer cell invasion by inhibiting ENO1-mediated GSK3β inactivation to promote SLUG protein ubiquitination and degradation. Moreover, chENO1-22 prevented lung tumor metastasis and prolonged survival in animal models. Taken together, these findings illuminate the molecular mechanisms underlying the function of ENO1 in lung cancer metastasis and support the therapeutic potential of a novel antibody targeting ENO1 for treating lung cancer. Significance: This study shows that ENO1 promotes lung cancer metastasis via HGFR and WNT signaling and introduces a novel anti-ENO1 antibody for potential therapeutic use in lung cancer.

NEDD4L inhibits glycolysis and proliferation of cancer cells in oral squamous cell carcinoma by inducing ENO1 ubiquitination and degradation

“… 20 , 21 In lung cancer, for instance, ENO1 knockdown inhibited cancer cell proliferation and invasiveness, while ENO1 overexpression facilitated these processes. 22 Besides its function in glycolysis, ENO1 is also expressed as a cell surface plasminogen receptor and facilitates cancer cell adhesion and metastasis. 23 , 24 Interestingly, a previous work found that ENO1 expression was elevated in OSCC and increased cell proliferation, with circ-angiomotin like 1 acting as the upstream mediator.…”

Prognostic Value of a Glycolytic Signature and Its Regulation by Y-Box-Binding Protein 1 in Triple-Negative Breast Cancer

“…Previous studies, including ours, reported that overexpression of glucose transporter 3 (GLUT3) promoted the EMT and invasiveness of glioma, colon, and breast cancer cells [37][38][39]. Additionally, ENO1 and LDHA were reported to promote the EMT and stemness in lung and breast cancer cells [40,41], suggesting that upregulation of glycolytic genes by YBX1 plays a crucial role in promoting tumor aggressiveness. In addition, YBX1 transcriptionally regulates a subset of mRNAs involved in the EMT, and YBX1 directly activates cap-independent translation of Snail [27].…”

Identification and validation of serum autoantibodies in children with B-cell acute lymphoblastic leukemia by serological proteome analysis

“…One of two proteins, α-enolase, found on the surface of cells, was is involved in several key biological processes of cancer, including proliferation, migration and invasion [ 36 , 37 ]. According to previous reports, α-enolase was overexpressed in multiple tumors, including lung cancer [ 38 ], hepatocellular carcinoma [ 39 ], pancreatic cancer [ 40 ], and gastric cancer patients [ 41 ], and was proposed as a biomarker for early detection or prognosis [ 42 ].…”

“…A recent study demonstrated that α-enolase and Annexin A1 autoantibodies could enhance diagnostic performance in lung cancers by combining CEA and CA125 [ 29 ]. Another study suggested that α-enolase could accelerate metastasis of lung cancer cell through HGFR and WNT signaling pathway, and presented a new antibody targeting α-enolase in lung cancer [ 37 ]. In multiple myeloma, α-enolase expression negatively correlated with overall survival, and targeting α-enolase could enhance immunity and improve outcome [ 46 ].…”