A recent study published in Engineering has shed new light on the mechanisms underlying the metastasis of head and neck squamous cell carcinoma (HNSCC). The research identified enolase 2 (ENO2), a crucial glycolytic enzyme, as a significant factor associated with lymphatic metastasis in HNSCC.

HNSCC is an aggressive cancer with a relatively low 5-year overall survival rate. Cervical lymph node metastasis is a major cause of cancer-related death in HNSCC patients, and effective therapies for metastatic HNSCC are currently lacking. Therefore, understanding the molecular mechanisms of HNSCC metastasis is of great significance.

The research team, through the integration of tumor databases, public datasets, and clinical relevance analysis, found that high ENO2 expression was positively correlated with lymph node (LN) metastasis in HNSCC. ENO2 overexpression promoted the migration and invasion of HNSCC cells both in vitro and in vivo, and this effect was mediated by the epithelial-mesenchymal (EMT) transition.

Further studies revealed that ENO2-mediated HNSCC metastasis was associated with M2 macrophage polarization. ENO2 regulated M2 macrophage polarization through its metabolite phosphoenolpyruvate (PEP). PEP could increase histone H3 lysine 18 lactylation (H3K18la) levels by inhibiting the catalytic activity of histone deacetylase 1 (HDAC1). The increased H3K18la enrichment in the promoter region of M2 macrophage-related genes promoted M2 macrophage polarization.

Moreover, PEP-mediated polarized macrophages enhanced the EMT and migration of HNSCC cells. The cytokine TGF-β released by polarized macrophages interacted with its receptor TGFβR1 on tumor cells, promoting EMT and migration, which may lead to tumor metastasis.

Importantly, pharmacological inhibition of ENO2 with POMHEX effectively reversed M2 macrophage polarization and inhibited HNSCC lymphatic metastasis in mouse models. This finding suggests that POMHEX could be a potential therapeutic approach for managing HNSCC metastasis.

This study elucidated the role of ENO2 in modulating macrophage polarization and contributing to HNSCC metastasis. It also revealed the mechanism by which ENO2-derived PEP regulates histone modification and macrophage polarization. These findings provide novel mechanistic insights into HNSCC lymphatic metastasis and offer potential therapeutic targets for metastatic HNSCC.

The paper “Cancer ENO2 Induces Histone Lactylation-Mediated M2 Macrophage Polarization and Facilitates Metastasis of Head and Neck Squamous Cell Carcinoma,” authored by henran Wang, Lin Tan, Maohua Huang, Yuning Lin, Minxiang Cai, Lijuan Deng, Xinpeng Hu, Shenghui Qiu, Xiaoting Chen, Yiming Zhang, Xiaomei Luo, Changzheng Shi, Minfeng Chen, Wencai Ye, Junqiu Zhang, Dongmei Zhang, Xiangning Liu. Full text of the open access paper: https://doi.org/10.1016/j.eng.2024.11.036.