ABSTRACT
KDM2A is a histone demethylase, which primarily catalyzes the demethylation of H3K36me2. Abnormal expression of KDM2A is observed in many types of cancers; however, the molecular events connected to KDM2A expression remain unclear. We report that KDM2A performs an oncogenic function in esophageal squamous cell carcinoma (ESCC) and is robustly expressed in ESCC cells. ShRNA-mediated knockdown of KDM2A resulted in a significant inhibition of the malignant phenotype of ESCC cell lines, whereas ectopic expression of KDM2A showed the opposite effect. We also analyzed the function of KDM2A using a CRISPR-CAS9 depletion system and subsequent rescue experiment, which also indicated a cancerous role of KDM2A. Interestingly, analysis of the gene expression network controlled by KDM2A using RNA-seq revealed an unexpected feature: KDM2A could induce expression of a set of well-documented oncogenic genes, including IL6 and LAT2, while simultaneously suppressing another set of oncogenes, including MAT2A and HMGCS1. Targeted inhibition of the upregulated oncogene in the KDM2A-depleted cells led to a synergistic suppressive effect on the malignant phenotype of ESCC cells. Our results revealed the dual role of KDM2A in ESCC cells, which may have therapeutic implications.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , F-Box Proteins , Carcinogenesis/genetics , Cell Line, Tumor , Cell Movement , Cell Proliferation/genetics , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/genetics , F-Box Proteins/genetics , F-Box Proteins/metabolism , Gene Expression Regulation, Neoplastic , Humans , Jumonji Domain-Containing Histone Demethylases/genetics , Jumonji Domain-Containing Histone Demethylases/metabolism , Methionine Adenosyltransferase/metabolismABSTRACT
OBJECTIVE: To study on invasion and metastasis-associated genes of lung cancer related with NM23-H1 gene. METHODS: Human gene expression chip based on the subtracted cDNA libraries was constructed. After microarray hybridization, clones sequencing, sequence homology search, the information of differently expressed genes in human large cell lung cancer cell line of L9981 and L9981-nm23-H1 were obtained and then further confirmed by real-time quantitative PCR. RESULTS: Gene expression profiling chips of differently expressed genes in human large cell lung cancer cell line L9981 and L9981-nm23-H1 were successfully constructed. After microarray hybridization, sequence homology search, 19 differentially expressed genes were observed. After real-time quantitative PCR evaluation, we found that the mRNA of 8 genes including PSMA7, SBDS, ODC1, YARS, CSDA, PTP4A1, SHPRH and TOMM7 was up-regulated in the cell line of L9981 after transfected with NM23-H1 gene, whereas the mRNA of PKM2 and GMNN was down-regulated. CONCLUSION: NM23-H1 gene may be the upstream regulator of metastasis-associated genes, which can regulate the downstream genes to achieve a series of lung cancer metastatic potential.
