EXT1 methylation promotes proliferation and migration and predicts the clinical outcome of non-small cell lung carcinoma via WNT signalling pathway.

Affiliation

Kong W(1), Chen Y(1), Zhao Z(1), Zhang L(1), Lin X(2), Luo X(3), Wang S(4)(5), Song Z(6)(7)(8), Lin X(9), Lai G(1), Yu Z(10).
Author information:
(1)Department of Respiratory Medicine and Critical Care Medicine, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, China.
(2)Laboratory of Radiation Oncology and Radiobiology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, China.
(3)Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.
(4)Department of Urology, 900th Hospital of the Joint Logistics Team Support Force, Fujian Medical University, Fuzhou, China.
(5)Fujian Key Laboratory of Transplant Biology, Affiliated Dongfang Hospital, Xiamen University School of Medicine, Fuzhou, China.
(6)Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, China.
(7)Department of Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China.
(8)Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
(9)Medical Oncology, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, China.
(10)Department of Respiratory Medicine and Critical Care Medicine, The 900th Hospital of Joint Logistic Support Force, PLA, Fujian Medical University,Affiliated Dongfang Hospital, Xiamen University School of Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.

Abstract

DNA methylation is important for lung cancer prognosis. In this work, it is aimed to seek novel biomarkers with DNA methylation-expression-pathway pattern and explore its underlying mechanism. Prognostic DNA methylation sites and mRNAs were screened in NSCLC data set from TCGA, and further validated using the samples retrospectively collected, and EXT1 was identified as a potential target. Gene body methylation of three CpG sites (cg03276982, cg11592677, cg16286281) on EXT1 was significantly associated with clinical outcome, and the EXT1 gene expression also predicted prognosis. The expression level of EXT1 was also correlated with its DNA methylation level. This observation was further validated in a new data set consist of 170 samples. Knocking down of EXT1 resulted in decreased proliferation and migration. EXT1 targets were analysed using GSEA. It is found that the WNT signalling is the potential downstream target of EXT1. Further analyses revealed that the EXT1 targets the beta-catenin and effect migration rate of NSCLC cell lines. The WNT signalling inhibitor, XAV-939, effectively disrupted the migration promotion effect induced by EXT1. In summary, EXT1 methylation regulates the gene expression, effects the proliferation and migration via WNT pathway and predicted a poor prognosis for NSCLC.