An exome-wide rare variant analysis of Korean men identifies three novel genes predisposing to prostate cancer

Oh, Jong Jin; Shivakumar, Manu; Miller, Jason E.; Verma, Shefali S.; Lee, Hakmin; Hong, Sung Kyu; Lee, Sang Eun; Lee, Younghee; Lee, Soo Ji; Sung, Joohon; Kim, Dokyoon; Byun, Seok Soo

doi:10.1038/s41598-019-53445-2

Cited by 8 publications

(6 citation statements)

References 61 publications

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“…As is known, the short arm of chromosome 3 is the most important region contributing to the pathogenesis of RCC, for the reason that several tumor suppressor genes, like VHL, SETD2, and PBRM1, are identified within this region [ 26 ]. ENTPD3-AS1 was reported to be significantly associated with prostate cancer [ 27 ]. A locus (rs193921050) in ENTPD3-AS1 has been reported for “malignant tumor of the prostate” in ClinVar with uncertain clinical significance [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling

Wang

Zou

et al. 2021

Cell Death Dis

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Over the last decade, more than 10 independent SNPs have been discovered to be associated with the risk of renal cell carcinoma among different populations. However, the biological functions of them remain poorly understood. In this study, we performed eQTL analysis, ChIP-PCR, luciferase reporter assay, and Cox regression analysis to identify the functional role and underlying mechanism of rs67311347 in RCC. The ENCORI database, which contains the lncRNA–miRNA–mRNA interactions, was used to explore the possible target miRNA of ENTPD3-AS1. The results showed that the G > A mutation of rs67311347 created a binding motif of ZNF8 and subsequently upregulated ENTPD3-AS1 expression by acting as an enhancer. The TCGA-KIRC and our cohorts both confirmed the downregulation of ENTPD3-AS1 in RCC tissues and demonstrated that increased ENTPD3-AS1 expression was associated with good OS and PFS. Furthermore, ENTPD3-AS1 interacted with miR-155-5p and activated the expression of HIF-1α, which was an important tumor suppressor gene in the development of RCC. The functional experiments revealed that overexpression of ENTPD3-AS1 inhibited cell proliferation in RCC cell lines and the effect could be rescued by knocking down HIF-1α. Our findings reveal that SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling.

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Section: Discussionmentioning

confidence: 99%

SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling

Wang

Zou

et al. 2021

Cell Death Dis

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“…Its research methods are used for mining and understanding the biological significance contained in massive data through various technologies and tools of computer science, biology and mathematics [ 44 ]. Many studies have shown that bioinformatics-based DNA methylation analysis is widely used for the identification of multiple human diseases, malignant tumor diagnosis, biomarker screening and targeted therapy [ 45 , 46 , 47 , 48 , 49 , 50 ]. The gold-standard method for quantitative interrogation of the methylation state of all CpG dinucleotides in a genome is Whole-Genome Bisulfite Sequencing (WGBS) [ 51 ].…”

Section: Introductionmentioning

confidence: 99%

Exploration of the Effect on Genome-Wide DNA Methylation by miR-143 Knock-Out in Mice Liver

Chen¹,

Luo²,

Liu³

et al. 2021

IJMS

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MiR-143 play an important role in hepatocellular carcinoma and liver fibrosis via inhibiting hepatoma cell proliferation. DNA methyltransferase 3 alpha (DNMT3a), as a target of miR-143, regulates the development of primary organic solid tumors through DNA methylation mechanisms. However, the effect of miR-143 on DNA methylation profiles in liver is unclear. In this study, we used Whole-Genome Bisulfite Sequencing (WGBS) to detect the differentially methylated regions (DMRs), and investigated DMR-related genes and their enriched pathways by miR-143. We found that methylated cytosines increased 0.19% in the miR-143 knock-out (KO) liver fed with high-fat diet (HFD), compared with the wild type (WT). Furthermore, compared with the WT group, the CG methylation patterns of the KO group showed lower CG methylation levels in CG islands (CGIs), promoters and hypermethylation in CGI shores, 5′UTRs, exons, introns, 3′UTRs, and repeat regions. A total of 984 DMRs were identified between the WT and KO groups consisting of 559 hypermethylation and 425 hypomethylation DMRs. Furthermore, DMR-related genes were enriched in metabolism pathways such as carbon metabolism (serine hydroxymethyltransferase 2 (Shmt2), acyl-Coenzyme A dehydrogenase medium chain (Acadm)), arginine and proline metabolism (spermine synthase (Sms), proline dehydrogenase (Prodh2)) and purine metabolism (phosphoribosyl pyrophosphate synthetase 2 (Prps2)). In summary, we are the first to report the change in whole-genome methylation levels by miR-143-null through WGBS in mice liver, and provide an experimental basis for clinical diagnosis and treatment in liver diseases, indicating that miR-143 may be a potential therapeutic target and biomarker for liver damage-associated diseases and hepatocellular carcinoma.

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“…LncRNAs can serve as competing endogenous RNA (ceRNA) to regulate gene expression by competitively binding miRNAs [19]. ENTPD3-AS1 has been reported to be associated with prostate cancer susceptibility [20]. In contrast, ENTPD3-AS1 has also been regarded as a tumor suppressor in renal cell carcinoma by inhibiting miR-155/HIF axis [21].…”

Section: Discussionmentioning

confidence: 99%

Downregulated antisense lncRNA ENTPD3-AS1 contributes to the development of lung adenocarcinoma

Chiang

2024

Am J Cancer Res

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The poor outcome of patients with lung adenocarcinoma (LUAD) highlights the importance to identify novel effective prognostic markers and therapeutic targets. Long noncoding RNAs (lncRNAs) have generally been considered to serve important roles in tumorigenesis and the development of various types of cancer, including LUAD. Here, we aimed to investigate the role of ENTPD3-AS1 (ENTPD3 Antisense RNA 1) in LUAD and to explore its potential mechanisms by performing comprehensive bioinformatic analyses. The regulatory effect of ENTPD3-AS1 on the expression of NR3C1 was validated by siRNA-based silencing. The effect of miR-421 on the modulation of NR3C1 was determined by miRNA mimics and inhibitors transfection. ENTPD3-AS1 was expressed at lower levels in tumor parts and negatively correlated with unfavorable prognosis in LUAD patients. It exerted functions as a tumor suppressor gene by competitively binding to oncomir, miR-421, thereby attenuating NR3C1 expression. Transfection of lung cancer A549 cells with miR-421 mimics decreased the expression of NR3C1. Transfection of lung cancer A549 cells with miR-421 inhibitors increased the expression of NR3C1 with lower cellular functions as proliferation and migration via epithelial-mesenchymal transition. In addition, inhibition of ENTPD3-AS1 by siRNA transfection decreased the levels of NR3C1, supporting the ENTPD3-AS1/miR-421/NR3C1 cascade. Moreover, the bioinformatic analysis also showed that ENTPD3-AS1 could interact with the RNA-binding proteins (RBPs), CELF2 and QKI, consequently regulating RNA expression and processing. Taken together, we identified that ENTPD3-AS1 and its indirect target NR3C1 can act as novel biomarkers for determining the prognosis of patients with LUAD, and further study is required.

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An exome-wide rare variant analysis of Korean men identifies three novel genes predisposing to prostate cancer

Cited by 8 publications

References 61 publications

SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling

SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling

Exploration of the Effect on Genome-Wide DNA Methylation by miR-143 Knock-Out in Mice Liver

Downregulated antisense lncRNA ENTPD3-AS1 contributes to the development of lung adenocarcinoma

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