Silencing of tumor-suppressive NR_023387 in renal cell carcinoma via promoter hypermethylation and HNF4A deficiency

Dysregulation of the epigenetic status of long noncoding RNAs (lncRNAs) has been linked to diverse human diseases including human cancers. However, the landscape of the whole-genome methylation profile of lncRNAs and the precise roles of these lncRNAs remain elusive in renal cell carcinoma (RCC). We first examined lncRNA expression profiles in RCC tissues and corresponding adjacent normal tissues (NTs) to identify the lncRNA signature of RCC, then lncRNA Promoter Microarray was performed to depict the whole-genome methylation profile of lncRNAs in RCC. Combined analysis of the lncRNAs expression profiles and lncRNAs Promoter Microarray identified a series of downregulated lncRNAs with hypermethylated promoter regions, including NR_023387. Quantitative real-time polymerase chain reaction (RT-PCR) implied that NR_023387 was significantly downregulated in RCC tissues and cell lines, and lower expression of NR_023387 was correlated with shorter overall survival. Methylation-specific PCR, MassARRAY, and demethylation drug treatment indicated that hypermethylation in the NR_023387 promoter contributed to its silencing in RCC. Besides, HNF4A regulated the expression of NR_023387 via transcriptional activation. Functional experiments demonstrated NR_023387 exerted tumor-suppressive roles in RCC via suppressing the proliferation, migration, invasion, tumor growth, and metastasis of RCC. Furthermore, we identified MGP as a putative downstream molecule of NR_023387, which promoted the epithelial-mesenchymal transition of RCC cells. Our study provides the first whole-genome lncRNA methylation profile in RCC. Our combined analysis identifies a tumor-suppressive and prognosis-related lncRNA NR_023387, which is silenced in RCC via promoter hypermethylation and HNF4A deficiency, and may exert its tumor-suppressive roles by downregulating the oncogenic MGP.