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Rs2853677 modulates Snail1 binding to the TERT enhancer and affects lung adenocarcinoma susceptibility.

ABSTRACT: Genome wide association studies (GWAS) have shown that SNPs in non-coding regions are associated with inherited susceptibility to cancer. The effect of one single SNP, however, is weak. To identify potential co-factors of SNPs, we investigated the underlying mechanism by which SNPs affect lung cancer susceptibility. We found that rs2853677 is located within the Snail1 binding site in a TERT enhancer. This enhancer increases TERT transcription when juxtaposed to the TERT promoter. The binding of Snail1 to the enhancer disrupts enhancer-promoter colocalization and silences TERT transcription. The high risk variant of rs2853677 disrupts the Snail1 binding site and derepresses TERT expression in response to Snail1 upregulation, thus increasing lung adenocarcinoma susceptibility. Our data suggest that Snail1 may be a co-factor of rs2853677 for predicting lung adenocarcinoma susceptibility and prognosis.

SUBMITTER: Li X

PROVIDER: S-EPMC5122352 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Rs2853677 modulates Snail1 binding to the TERT enhancer and affects lung adenocarcinoma susceptibility.

Li Xiaoting X Xu Xing X Fang Jiali J Wang Lin L Mu Yanchao Y Zhang Peng P Yao Zhi Z Ma Zhenyi Z Liu Zhe Z

Oncotarget 20160601 25

Genome wide association studies (GWAS) have shown that SNPs in non-coding regions are associated with inherited susceptibility to cancer. The effect of one single SNP, however, is weak. To identify potential co-factors of SNPs, we investigated the underlying mechanism by which SNPs affect lung cancer susceptibility. We found that rs2853677 is located within the Snail1 binding site in a TERT enhancer. This enhancer increases TERT transcription when juxtaposed to the TERT promoter. The binding of ...[more]

PMID: 27191258

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Project description:ObjectiveThe purpose of this study was to identify prognostic inflammatory markers regulated by enhancers in lung adenocarcinoma (LUAD).MethodsInflammatory indices of 490 LUAD patients in TCGA database were calculated using genomic variation analysis (GSVA). Patients were divided into high- and low-inflammatory index groups. Fraction of 22 infiltrating immune cells was estimated using the Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT). Gene set enrichment analysis (GSEA) was used to analyze gene enrichment. Differentially expressed genes were screened based on TCGA database. The H3K27ac ChIP-seq of A549 cells in GEO database (GSE42374) was analyzed to identify super enhancers. Kaplan-Meier method and multivariate Cox proportional hazards models were used for survival analysis. CCK8 and RT-qPCR were used for cellular level verification.ResultsInflammation was associated with better outcome in LUAD patients. Anti-cancer immune cell fractions were upregulated in high-inflammatory index group. Genes enriched in inflammation-related signaling pathways were positively correlated with high-inflammatory index group. A total of 146 upregulated genes regulated by enhancers were screened, of which five genes including GDF10, HPGDS, ABCA8, SLIT3 and ADAMTS8 had significant influence on prognosis. ChIP-seq analysis showed that TGFβ+TNFα treatment promoted the enhancer activation of the five genes. Cellular experiments revealed that there was no significant effect of TGFβ treatment on the five genes expression. TNFα treatment upregulated the five genes expression, while the BET-bromodomain inhibitor JQ1 restored the effect of TNFα. Overexpression of the five genes significantly inhibited the proliferation of A549 and H1299 cells.ConclusionGDF10, HPGDS, ABCA8, SLIT3 and ADAMTS8 were identified as enhancer-regulated prognostic inflammation-related biomarkers, and the expression of these genes inhibited proliferation of LUAD cells.

Dataset Information

Rs2853677 modulates Snail1 binding to the TERT enhancer and affects lung adenocarcinoma susceptibility.

Publications

Rs2853677 modulates Snail1 binding to the TERT enhancer and affects lung adenocarcinoma susceptibility.

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