RETRACTED: Silencing of tumor‐suppressive NR_023387 in renal cell carcinoma via promoter hypermethylation and HNF4A deficiency

Abstract

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 PromoterMicroarray 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 tumorsuppressive roles by downregulating the oncogenic MGP. K E Y W O R D SHNF4A, long noncoding RNA, matrix Gla protein, methylation, NR_023387, renal cell carcinoma

Histone deacetylase HDAC2 silencing prevents endometriosis by activating the HNF4A/ARID1A axis

“…Corroborating finding are identified in a previous study, which demonstrated that HNF4A is involved in the pathogenesis of endometriosis 9 . Moreover, it was reported in a prior research that HNF4A deficiency diminished renal cell carcinoma cell proliferation, migration and invasion 18 . Moreover, HNF4A upregulation could trigger inhibition of hepatocellular carcinoma proliferation 19 .…”

Dysregulation of Long Non-coding RNAs and mRNAs in Plasma of Clear Cell Renal Cell Carcinoma Patients Using Microarray and Bioinformatic Analysis

“…Furthermore, the samples used in these studies (19). Based on the lncRNA Promoter Microarray and combined analysis of the lncRNAs expression profiles, Zhou et al identified a series of down-regulated lncRNAs with hypermethylated promoter regions (24). To our best knowledge, few systemic studies have focused on the lncRNAs in plasma of ccRCC patients.…”

“…Over the past decades, several studies had focused on the expression profile of lncRNA in ccRCC tissues (14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Many lncRNAs are confirmed to be involved in the pathogenesis of ccRCC (19,21,23,24). Nevertheless, few studies have evaluated the roles of plasma lncRNAs in the diagnosis of ccRCC.…”

Controversial roles of hepatocyte nuclear receptor 4 α on tumorigenesis (Review)

“…Cyclin D1 was also demonstrated to directly bind to HNF4α and cause a decrease in downstream genes expression (61). Previous studies in renal cell carcinoma reported that decreased HNF4α expression is positively correlated with e-cadherin expression, suggesting a poor prognosis in patients (62)(63)(64). Furthermore, HNF4α expression is blocked by mutated IDH, which could promote biliary cancer progression (65).…”