A common regulatory variant in SLC35B4 influences the recurrence and survival of prostate cancer
Journal
Journal of Cellular and Molecular Medicine
Journal Volume
22
Journal Issue
7
Pages
3661-3670
Date Issued
2018
Author(s)
Huang E.Y.
Chang Y.-J.
Huang S.-P.
Lin V.C.
Yu C.-C.
Yin H.-L.
Chang T.-Y.
Lu T.-L.
Bao B.-Y.
Abstract
Single nucleotide polymorphisms (SNPs) within the regulatory elements of a gene can alter gene expression, making these SNPs of prime importance for candidate gene association studies. We aimed to determine whether such regulatory variants are associated with clinical outcomes in three cohorts of patients with prostate cancer. We used RegulomeDB to identify potential regulatory variants based on in silico predictions and reviewed genome-wide experimental findings. Overall, 131 putative regulatory SNPs with the highest confidence score on predicted functionality were investigated in two independent localized prostate cancer cohorts totalling 458 patients who underwent radical prostatectomy. The statistically significant SNPs identified in these two cohorts were then tested in an additional cohort of 504 patients with advanced prostate cancer. We identified one regulatory SNPs, rs1646724, that are consistently associated with increased risk of recurrence in localized disease (P?=.003) and mortality in patients with advanced prostate cancer (P?=.032) after adjusting for known clinicopathological factors. Further investigation revealed that rs1646724 may affect expression of SLC35B4, which encodes a glycosyltransferase, and that down-regulation of SLC35B4 by transfecting short hairpin RNA in DU145 human prostate cancer cell suppressed proliferation, migration and invasion. Furthermore, we found increased SLC35B4 expression correlated with more aggressive forms of prostate cancer and poor patient prognosis. Our study provides robust evidence that regulatory genetic variants can affect clinical outcomes. ? 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Subjects
multi-stage association study; prognosis; prostate cancer; regulatory variant; SLC35B4
SDGs
Other Subjects
genomic DNA; prostate specific antigen; solute carrier protein; solute carrier protein 35 B4; unclassified drug; nucleotide transporter; SLC35B4 protein, human; adult; Article; cancer growth; cancer localization; cancer prognosis; cancer recurrence; cancer staging; cancer survival; cell invasion; cell migration; cell proliferation; cohort analysis; controlled study; DU145 cell line; gene; gene expression; gene frequency; gene knockdown; genetic variability; genotyping technique; Gleason score; human; human cell; human tissue; immunohistochemistry; major clinical study; male; overall survival; PC-3 [Human prostate carcinoma] cell line; priority journal; prostate cancer; prostatectomy; protein expression; single nucleotide polymorphism; SLC35B4 gene; tissue microarray; Western blotting; aged; clinical trial; epidemiology; gene expression regulation; genetics; middle aged; mortality; multicenter study; pathology; prostate tumor; single nucleotide polymorphism; Taiwan; tumor recurrence; Aged; Cohort Studies; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Nucleotide Transport Proteins; Polymorphism, Single Nucleotide; Prostatectomy; Prostatic Neoplasms; Taiwan; Tissue Array Analysis
Publisher
Blackwell Publishing Inc.
Type
journal article