PRMT5/Wnt4 axis promotes lymph-node metastasis and proliferation of laryngeal carcinoma

Nan Wang,Xiaohao Wang,Di Wu,Xuekui Liu,Qian Long,Honghong Yan,Zheng Zhao,Xiaoqi Chen,Wuguo Deng,Changlin Zhang

doi:10.1038/s41419-020-03064-x

Abstract

Metastasis is the main cause of laryngeal cancer-related death; its molecular mechanism remains unknown. Here we identify protein arginine methyltransferase 5 (PRMT5) as a new metastasis-promoting factor in laryngeal carcinoma, and explore its underlying mechanism of action in regulating laryngeal cancer progression. We illustrated that PRMT5 expression was positively correlated with tumor stages, lymphatic metastasis, and unfavorable outcome. Functional assays revealed that PRMT5 promoted laryngeal carcinoma cell proliferation, migration, and invasive capacity in vitro, as well as lymph-node metastasis in vivo. The ectopic expression of PRMT5 induced EMT with downregulation of E-cadherin and upregulation of N-cadherin, snail, and MMP9. Mechanistic results revealed that the metastatic effects could be attributed to PRMT5-mediated activation of Wnt signaling, and Wnt4 is an important driver of Wnt/β-catenin signaling pathway. Wnt4 silencing could reverse PRMT5-induced cell proliferation, migration, and invasion capacities. Furthermore, inhibition of the Wnt/β-catenin signaling pathway abolished the effect of PRMT5-induced proliferation, whereas activation of the pathway enhanced the effect of PRMT5 overexpression on cell proliferation. These results demonstrated that the oncogenic role of PRMT5 could be attributed to PRMT5/Wnt4 axis-mediated activation of the Wnt/β-catenin signaling pathway. PRMT5 may serve as a novel prognostic marker and a therapeutic target for lymphatic metastasis of laryngeal carcinoma.

Highlights

As a malignancy in the head and neck region, laryngeal carcinoma represents the second most commonly occurring cancer of the respiratory tract, >95% of which is squamous cell carcinoma
To identify whether Protein arginine methyltransferase 5 (PRMT5) was expressed in laryngeal carcinoma and correlated with patient prognosis, a cohort of clinical samples (n = 88, Table S1) from laryngeal carcinoma and matched normal adjacent tissues were analyzed by immunohistochemistry
A 123-case cohort from The Cancer Genome Atlas (TCGA) database showed that PRMT5 expression was upregulated in the laryngeal carcinoma with lymph-node metastasis compared with the tissues without lymph-node metastasis (Fig. 1g, h)

Summary

Introduction

As a malignancy in the head and neck region, laryngeal carcinoma represents the second most commonly occurring cancer of the respiratory tract, >95% of which is squamous cell carcinoma. PRMT5 is overexpressed in a variety of cancers, and its activity is associated with cell transformation. PRMT5 overexpression or hyperactivation is observed in several tumor types, including acute myeloid leukemia, breast cancer, glioblastoma, lung, and prostate cancer, which facilitates tumor initiation and progression[11,12,13,14,15,16]. PRMT5 overexpression positively correlates with astrocytoma progression, and inversely correlates with survival[13]. Kryukov et al.[17] reported that PRMT5 repression induced tumor shrinkage and cell apoptosis. Depletion of PRMT5 in glioma cell lines failed to form tumors in mice engrafted intracranially with GBM xenografts[13], suggesting that

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