title: An NKX3.1 binding site polymorphism in the l-plastin promoter leads to differential gene expression in human prostate cancer.
abstract: The L-plastin gene is involved in the invasion and metastasis of prostate cancer. However, the molecular mechanisms underlying L-plastin transcription are unclear. We hypothesize that the occurrence of polymorphic genetic variations in the L-plastin promoter might affect an individual's susceptibility to prostate cancer. In this study, we identified a single nucleotide polymorphism (SNP) at position -1,687 in the L-plastin promoter by genotype sequencing. The SNP -1,687 showed different transcriptional activity in the luciferase assay in vitro. The TRANSFAC software was applied to predict the multiple cis-elements, and luciferase assay was used to further identify the L-plastin regulatory region. We performed EMSAs, supershift assays and ChIP-qPCR demonstrated that the transcriptional suppressor NKX3.1 binds to the SNP site of the L-plastin promoter. SNP -1,687 (T/T) led to an increase in the affinity of NKX3.1 for L-plastin promoter, resulted in lower levels of L-plastin RNA and protein expression. Furthermore, we collected and sequenced samples from 640 individuals (372 prostate cancer patients and 268 healthy controls) from 2000 to 2013. The results showed that SNP -1,687 (T/T) occurred more frequently in the healthy individuals than that in the prostate cancer patients compared to SNP -1,687 (C/C). Similarly, SNP -1,687 (T/T) genotype occurred more frequently compared to SNP -1,687 (C/C) genotype in the patients with low and moderately differentiated tumors. In conclusion, SNP -1,687, located in the NKX3.1 binding site within the L-plastin promoter, might reduce the expression of L-plastin and potentially decrease the tumorigenesis and progression of prostate cancer. This SNP could be a potential prognostic factor for prostate cancer.
authors.affiliation: Department of Urology, Sun Yat-Sen Memorial Hospital, Guangzhou, China.|Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
authors.forename: Changhao
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Sun Yat-Sen University Cancer Center State, Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Department of Urology, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
authors.forename: Wang
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Oncology, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Fangjian
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Urology, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
authors.forename: Guangzheng
authors.initials: G
authors.lastname: Zhong
authors.affiliation: Department of Urology, Sun Yat-Sen Memorial Hospital, Guangzhou, China.|Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Urology, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Dong
authors.affiliation: Department of Urology, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Mosaic Laboratories, Lake Forest, CA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Urology, Sun Yat-Sen Memorial Hospital, Guangzhou, China.|Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
authors.forename: Tianxin
authors.initials: T
authors.lastname: Lin
mesh_terms: D000483:Alleles; D001665:Binding Sites; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D055785:Gene Knockdown Techniques; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; C491178:NKX3-1 protein, human; D014157:Transcription Factors; C026742:plastin
keywords: L-plastin; NKX3.1; molecular regulation; prostate cancer; single nucleotide polymorphism