Targeting of EZH2 inhibits epithelial‑mesenchymal transition in head and neck squamous cell carcinoma via regulating the STAT3/VEGFR2 axis.

Minghui Zhao,Shanshan Sun,Lingping Kong,Xiaomeng Hu,Rui Jin,Yu Ren,Yini Xu,Chuanqiang Wu,Xuan Zhou,Lun Zhang,Jinliang Chen

doi:10.3892/ijo.2019.4880

Abstract

Tumor metastasis regulated by epithelial‑mesenchymal transition (EMT) plays a significant role in the development of human cancers, whereas the molecular mechanisms of this process in head and neck squamous cell carcinoma (HNSCC) remain elusive. In this study, we found that inhibition of enhancer of zeste homolog2 (EZH2) resulted in suppressed EMT in HNSCC invitro and invivo. We reported that signal transducer and activator of transcription factor3 (STAT3)/vascular endothelial growth factor receptor2 (VEGFR2) axis served as the downstream signaling of EZH2 and mediated EMT in HNSCC. EZH2 inhibition downregulated the expression of key molecules of the STAT3/VEGFR2 axis and EMT‑related markers, while the expression of E‑cadherin was upregulated in HNSCC cells. Targeting the EZH2/STAT3/VEGFR2 axis significantly reduced motility of HNSCC cells. Furthermore, EZH2 knockdown reduced the growth of xenograft HNSCC tumors via inhibiting the EZH2/STAT3/VEGFR2 axis. In conclusion, we proposed that EZH2 regulates EMT and tumor invasion and metastasis in HNSCC by governing the STAT3/VEGFR2 axis. These findings provide a rationale for developing novel strategies to treat invasive and metastatic HNSCC via targeting the EZH2/STAT3/VEGFR2 pathway.

Highlights

600,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed worldwide annually, making this cancer the sixth most common human malignancy [1]
We reported that an Enhancer of zeste homolog 2 (EZH2)‐centered axis regulates HNSCC progression, as manifested by our observations that targeting the EZH2/STAT3/vascular endothelial growth factor receptor 2 (VEGFR2) pathway suppresses HNSCC metastatic progression both in vitro and in vivo
Accumulating evidence suggests that EZH2 is closely related to Epithelial mesenchymal transition (EMT) in several cancer types [35], and our previous study demonstrated that EZH2 is upregulated in HNSCC and acts as a negative prognostic factor for patients with HNSCC [11]

Summary

Introduction

600,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed worldwide annually, making this cancer the sixth most common human malignancy [1]. Systemic therapies have been employed for treating this cancer with significant progress; the 5‐year overall survival remains low at ~50% [2], due to subsequent metastasis developed in such patients which accounts for the poor clinical outcome of HNSCC [2]. Epithelial mesenchymal transition (EMT), initially described in embryonic development, has been reported to be one of the most important mechanisms of cell migration and invasion in physiological and pathological processes, such as tissue repair, fibrosis and cancer progression [3]. Reports showed that EZH2 could regulate tumor angiogenesis [12], apoptosis [11], EMT [13], and cell migration and invasion [14,15]. EZH2 is a promising therapeutic target for treating HNSCC

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