Single-nucleotide polymorphism rs13426236 contributes to an increased prostate cancer risk via regulating MLPH splicing variant 4. Mol Carcinog 2020 Jan;59(1):45-55
Date
10/30/2019Pubmed ID
31659808Pubmed Central ID
PMC7219604DOI
10.1002/mc.23127Scopus ID
2-s2.0-85074694919 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
A prostate cancer risk single-nucleotide polymorphism (SNP), rs13426236, is significantly associated with melanophilin (MLPH) expression. To functionally characterize role of the rs13426236 in prostate cancer, we first performed splicing-specific expression quantitative trait loci analysis and refined the significant association of rs13426236 allele G with an increased expression of MLPH splicing transcript variant 4 (V4) (P = 7.61E-5) but not other protein-coding variants (V1-V3) (P > .05). We then performed an allele-specific reporter assay to determine if SNP-containing sequences functioned as an active enhancer. Compared to allele A, allele G of rs13426236 showed significantly higher luciferase activity on the promoter of the splicing transcript V4 (P < .03) but not on the promoter of transcript V1 (P > .05) in two prostate cancer cell lines (DU145 and 22Rv1). Cell transfection assays showed stronger effect of transcript V4 than V1 on promoting cell proliferation, invasion, and antiapoptotic activities. RNA profiling analysis demonstrated that transcript V4 overexpression caused significant expression changes in glycosylation/glycoprotein and metal-binding gene ontology pathways (FDR < 0.01). We also found that both transcripts V4 and V1 were significantly upregulated in prostate adenocarcinoma (P ≤ 2.49E-6) but only transcript V4 upregulation was associated with poor recurrence-free survival (P = .028, hazard ratio = 1.63, 95% confidence interval = 1.05-2.42) in The Cancer Genome Atlas data. This study provides strong evidence showing that prostate cancer risk SNP rs13426236 upregulates expression of MLPH transcript V4, which may function as a candidate oncogene in prostate cancer.
Author List
Xiao F, Zhang P, Wang Y, Tian Y, James M, Huang CC, Wang L, Wang LMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAlternative Splicing
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Humans
Male
Neoplasm Invasiveness
Polymorphism, Single Nucleotide
Prostatic Neoplasms
Protein Isoforms
Quantitative Trait Loci
Up-Regulation