Eno2, also known as neuron-specific enolase (NSE), is a crucial glycolytic enzyme. It is a cell-specific isoenzyme of enolase, with its expression being a late event in neural differentiation. Eno2 is highly specific for neurons and peripheral neuroendocrine cells, and it participates in the glycolytic pathway, which is fundamental for energy production in cells. Its overall biological importance lies in its roles in normal neural maturation and potential implications in various diseases [7].

In cancer research, Eno2 has been extensively studied. In colorectal cancer (CRC) mouse models, Eno2 overexpression induces neuroendocrine differentiation, promotes malignancy, and confers resistance to anti-angiogenic therapy. Mechanistically, the Eno2-derived metabolite phosphoenolpyruvate (PEP) inhibits histone deacetylase 1 (HDAC1) activity, activating the β-catenin pathway [1]. In head and neck squamous cell carcinoma (HNSCC), loss-of-function experiments showed that Eno2 is required for cell proliferation and glycolysis, partially by controlling PKM2 protein stability and its nuclear translocation [2]. In diffuse large B-cell lymphoma (DLBCL), DLBCL-derived exosomal Eno2 modulates macrophage polarization through reprogramming glycolysis via the GSK3β/β-catenin/c-Myc signaling pathway, promoting DLBCL progression [3]. In prostate cancer, although no KO/CKO mouse models were mentioned, human and in vitro studies suggest Eno2 may contribute to metastasis, possibly due to the unique metabolic features of prostate cancer at the advanced metastatic stage [4]. In CRC, Eno2 promotes metastasis by interacting with lncRNA CYTOR and activating YAP1-induced EMT, independent of glycolysis regulation [5]. In MSI-H CRC, functional experiments with Eno2 knockdown and overexpression demonstrated its role in promoting cell migration, invasion, glycolysis, and EMT [6]. In clear cell renal cell carcinoma (ccRCC), in vitro experiments confirmed that Eno2 promotes cell proliferation and migration, and its expression is positively correlated with immunosuppressive indicators [8].

In conclusion, Eno2 is a multifunctional glycolytic enzyme. Model-based research, especially in cancer, has revealed its roles in promoting cancer cell proliferation, migration, invasion, and in modulating the tumor microenvironment. These findings in various cancer types highlight the importance of Eno2 as a potential therapeutic target and prognostic biomarker.

References:

1. Wang, Chenran, Huang, Maohua, Lin, Yuning, Zhang, Dongmei, Ye, Wencai. 2023. ENO2-derived phosphoenolpyruvate functions as an endogenous inhibitor of HDAC1 and confers resistance to antiangiogenic therapy. In Nature metabolism, 5, 1765-1786. doi:10.1038/s42255-023-00883-y. https://pubmed.ncbi.nlm.nih.gov/37667133/

2. Gao, Lixia, Yang, Fan, Tang, Dianyong, Chen, Zhongzhu, Teng, Yong. 2023. Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development. In Journal of experimental & clinical cancer research : CR, 42, 1. doi:10.1186/s13046-022-02574-0. https://pubmed.ncbi.nlm.nih.gov/36588153/

3. Shao, Ruonan, Liu, Chengcheng, Xue, Ruifeng, Tang, Hailin, Liu, Wenjian. 2024. Tumor-derived Exosomal ENO2 Modulates Polarization of Tumor-associated Macrophages through Reprogramming Glycolysis to Promote Progression of Diffuse Large B-cell Lymphoma. In International journal of biological sciences, 20, 848-863. doi:10.7150/ijbs.91154. https://pubmed.ncbi.nlm.nih.gov/38250157/

4. Zhou, Yuhan, Zeng, Feier, Richards, Gareth Owain, Wang, Ning. 2024. ENO2, a Glycolytic Enzyme, Contributes to Prostate Cancer Metastasis: A Systematic Review of Literature. In Cancers, 16, . doi:10.3390/cancers16142503. https://pubmed.ncbi.nlm.nih.gov/39061144/

5. Lv, Chunwei, Yu, Hongfei, Wang, Keyi, Lai, Maode, Zhang, Honghe. 2022. ENO2 Promotes Colorectal Cancer Metastasis by Interacting with the LncRNA CYTOR and Activating YAP1-Induced EMT. In Cells, 11, . doi:10.3390/cells11152363. https://pubmed.ncbi.nlm.nih.gov/35954207/

6. Cai, Junwen, Yang, Yuting, Zhang, Leilei, Li, Liyi, Zheng, Xiaoqun. 2024. Investigation of ENO2 as a promising novel marker for the progression of colorectal cancer with microsatellite instability-high. In BMC cancer, 24, 573. doi:10.1186/s12885-024-12332-4. https://pubmed.ncbi.nlm.nih.gov/38724951/

7. Isgrò, Maria Antonietta, Bottoni, Patrizia, Scatena, Roberto. . Neuron-Specific Enolase as a Biomarker: Biochemical and Clinical Aspects. In Advances in experimental medicine and biology, 867, 125-43. doi:10.1007/978-94-017-7215-0_9. https://pubmed.ncbi.nlm.nih.gov/26530364/

8. Chen, Wei-Jie, Yang, Wei, Gong, Min, Pan, Xiu-Wu, Cui, Xin-Gang. 2022. ENO2 affects the EMT process of renal cell carcinoma and participates in the regulation of the immune microenvironment. In Oncology reports, 49, . doi:10.3892/or.2022.8470. https://pubmed.ncbi.nlm.nih.gov/36562383/