GALNT6 promotes invasion and metastasis of human lung adenocarcinoma cells through O-glycosylating chaperone protein GRP78

Jing Song,Junxia Hao,Yang Zhou,Mingliang Ye,Jianzhen Wang,Wenwen Liu,Xinri Zhang,Qi Wang,Jing Ben,Xiaohui Du,Xin You,Yingyan Wang

doi:10.1038/s41419-020-2537-6

Abstract

Lung adenocarcinoma remains a threat to human health due to its high rate of recurrence and distant metastasis. However, the molecular mechanism underlying lung adenocarcinoma metastasis remains yet incompletely understood. Here, we show that upregulated expression of polypeptide N-acetylgalactosaminyltransferase6 (GALNT6) in lung adenocarcinoma is associated with lymph node metastasis and poor prognosis. In lung adenocarcinoma cells, GALNT6 over-expression promoted epithelial–mesenchymal transition (EMT), wound healing, and invasion which could be significantly reversed by GALNT6 silencing. GALNT6 silencing also mitigated the metastasis of lung adenocarcinoma and prolonged the survival of xenograft tumor-bearing mice. Furthermore, GALNT6 directly interacted with, and O-glycosylated chaperone protein GRP78, which promoted EMT by enhancing the MEK1/2/ERK1/2 signaling in lung cancer cells. Therefore, GALNT6 is emerging as novel positive regulator for the malignancy of human lung adenocarcinoma. Targeting GALNT6-GRP78-MEK1/2/ERK1/2 may thus represent a new avenue to develop therapeutics against lung cancer metastasis.

Highlights

Lung adenocarcinoma is a common malignancy in the world, and has a high mortality rate[1]
Increased GALNT6 expression is associated with poor prognosis of lung adenocarcinoma patients
Stratification analyses showed that higher GALNT6 expression in lung adenocarcinoma was significantly correlated with higher T stage (P = 0.017), positive lymph node metastasis (P = 0.024) and higher

Summary

Introduction

Lung adenocarcinoma is a common malignancy in the world, and has a high mortality rate[1]. Standard treatments for lung adenocarcinoma have achieved some progress, its high rates of recurrence and distant metastasis make it a major threat to patient health[2,3,4,5,6]. It is important to better is an enzyme for O-glycosylation and its expression is increased in some human cancers, including lung adenocarcinoma[7,8,9,10]. Previous studies suggest that GALNT6 may be important for cancer formation, progression, metastasis, and prognosis[10,11,12,13,14]. High GALNT6 expression is associated with the recurrence, lymph node metastasis, and chemoresistance of ovarian cancer[11]. GALNT6 is implicated in the epithelial–mesenchymal transition (EMT) process which

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Results

Conclusion