A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression

Shusuke Akamatsu, Ryo Takata, Kyota Ashikawa, Naoya Hosono, Naoyuki Kamatani, Tomoaki Fujioka, Osamu Ogawa, Michiaki Kubo, Yusuke Nakamura, Hidewaki Nakagawa

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Genome-wide association studies (GWAS) identified multiple susceptible loci for prostate cancer (PC), and recent GWAS implicated that a common variant rs1512268 on chromosome 8p21 is associated with PC susceptibility, which is located at 14 kb downstream of a prostate tumor suppressor gene NKX3.1. To clarify a susceptibility gene and functional variants in this locus, we performed re-sequencing and fine mapping of this region and identified 12 candidates of functional single nucleotide polymorphisms that were absolutely linked with each other. Screening of these variants by RNA stability assay, electrophoretic mobility shift assay (EMSA) and reporter assay indicated that rs11781886 in the 5′-UTR of NKX3.1 displayed different binding affinity to nuclear proteins between the alleles, and that the transcriptional activity of the NKX3.1 promoter was significantly lower in the susceptible allele of this variant. Sp1 was determined to be the transcription factor that binds to the susceptible G allele, but not to the non-susceptible A allele. Allele-specific transcript quantification (ASTQ) and quantitative PCR analyses showed that the expression of NKX3.1 in the prostate was significantly lower in the subjects with the haplotype carrying the susceptible allele. These results suggest that the functional variant rs11781886 in the 5′-UTR of NKX3.1 can affect its transcription by altering the binding affinity of a transcriptional factor Sp1, and might result in PC susceptibility by lowering expression of NKX3.1 in the prostate.

Original languageEnglish
Article numberddq350
Pages (from-to)4265-4272
Number of pages8
JournalHuman molecular genetics
Volume19
Issue number21
DOIs
Publication statusPublished - 17-08-2010
Externally publishedYes

Fingerprint

Prostatic Neoplasms
Down-Regulation
Alleles
Prostate
5' Untranslated Regions
Genome-Wide Association Study
RNA Stability
Electrophoretic Mobility Shift Assay
Nuclear Proteins
Tumor Suppressor Genes
Haplotypes
Single Nucleotide Polymorphism
Transcription Factors
Chromosomes
Polymerase Chain Reaction
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Akamatsu, S., Takata, R., Ashikawa, K., Hosono, N., Kamatani, N., Fujioka, T., ... Nakagawa, H. (2010). A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression. Human molecular genetics, 19(21), 4265-4272. [ddq350]. https://doi.org/10.1093/hmg/ddq350
Akamatsu, Shusuke ; Takata, Ryo ; Ashikawa, Kyota ; Hosono, Naoya ; Kamatani, Naoyuki ; Fujioka, Tomoaki ; Ogawa, Osamu ; Kubo, Michiaki ; Nakamura, Yusuke ; Nakagawa, Hidewaki. / A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression. In: Human molecular genetics. 2010 ; Vol. 19, No. 21. pp. 4265-4272.
@article{60ceb6c34b904cb19d6cdf063e864e1f,
title = "A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression",
abstract = "Genome-wide association studies (GWAS) identified multiple susceptible loci for prostate cancer (PC), and recent GWAS implicated that a common variant rs1512268 on chromosome 8p21 is associated with PC susceptibility, which is located at 14 kb downstream of a prostate tumor suppressor gene NKX3.1. To clarify a susceptibility gene and functional variants in this locus, we performed re-sequencing and fine mapping of this region and identified 12 candidates of functional single nucleotide polymorphisms that were absolutely linked with each other. Screening of these variants by RNA stability assay, electrophoretic mobility shift assay (EMSA) and reporter assay indicated that rs11781886 in the 5′-UTR of NKX3.1 displayed different binding affinity to nuclear proteins between the alleles, and that the transcriptional activity of the NKX3.1 promoter was significantly lower in the susceptible allele of this variant. Sp1 was determined to be the transcription factor that binds to the susceptible G allele, but not to the non-susceptible A allele. Allele-specific transcript quantification (ASTQ) and quantitative PCR analyses showed that the expression of NKX3.1 in the prostate was significantly lower in the subjects with the haplotype carrying the susceptible allele. These results suggest that the functional variant rs11781886 in the 5′-UTR of NKX3.1 can affect its transcription by altering the binding affinity of a transcriptional factor Sp1, and might result in PC susceptibility by lowering expression of NKX3.1 in the prostate.",
author = "Shusuke Akamatsu and Ryo Takata and Kyota Ashikawa and Naoya Hosono and Naoyuki Kamatani and Tomoaki Fujioka and Osamu Ogawa and Michiaki Kubo and Yusuke Nakamura and Hidewaki Nakagawa",
year = "2010",
month = "8",
day = "17",
doi = "10.1093/hmg/ddq350",
language = "English",
volume = "19",
pages = "4265--4272",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "21",

}

Akamatsu, S, Takata, R, Ashikawa, K, Hosono, N, Kamatani, N, Fujioka, T, Ogawa, O, Kubo, M, Nakamura, Y & Nakagawa, H 2010, 'A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression', Human molecular genetics, vol. 19, no. 21, ddq350, pp. 4265-4272. https://doi.org/10.1093/hmg/ddq350

A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression. / Akamatsu, Shusuke; Takata, Ryo; Ashikawa, Kyota; Hosono, Naoya; Kamatani, Naoyuki; Fujioka, Tomoaki; Ogawa, Osamu; Kubo, Michiaki; Nakamura, Yusuke; Nakagawa, Hidewaki.

In: Human molecular genetics, Vol. 19, No. 21, ddq350, 17.08.2010, p. 4265-4272.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression

AU - Akamatsu, Shusuke

AU - Takata, Ryo

AU - Ashikawa, Kyota

AU - Hosono, Naoya

AU - Kamatani, Naoyuki

AU - Fujioka, Tomoaki

AU - Ogawa, Osamu

AU - Kubo, Michiaki

AU - Nakamura, Yusuke

AU - Nakagawa, Hidewaki

PY - 2010/8/17

Y1 - 2010/8/17

N2 - Genome-wide association studies (GWAS) identified multiple susceptible loci for prostate cancer (PC), and recent GWAS implicated that a common variant rs1512268 on chromosome 8p21 is associated with PC susceptibility, which is located at 14 kb downstream of a prostate tumor suppressor gene NKX3.1. To clarify a susceptibility gene and functional variants in this locus, we performed re-sequencing and fine mapping of this region and identified 12 candidates of functional single nucleotide polymorphisms that were absolutely linked with each other. Screening of these variants by RNA stability assay, electrophoretic mobility shift assay (EMSA) and reporter assay indicated that rs11781886 in the 5′-UTR of NKX3.1 displayed different binding affinity to nuclear proteins between the alleles, and that the transcriptional activity of the NKX3.1 promoter was significantly lower in the susceptible allele of this variant. Sp1 was determined to be the transcription factor that binds to the susceptible G allele, but not to the non-susceptible A allele. Allele-specific transcript quantification (ASTQ) and quantitative PCR analyses showed that the expression of NKX3.1 in the prostate was significantly lower in the subjects with the haplotype carrying the susceptible allele. These results suggest that the functional variant rs11781886 in the 5′-UTR of NKX3.1 can affect its transcription by altering the binding affinity of a transcriptional factor Sp1, and might result in PC susceptibility by lowering expression of NKX3.1 in the prostate.

AB - Genome-wide association studies (GWAS) identified multiple susceptible loci for prostate cancer (PC), and recent GWAS implicated that a common variant rs1512268 on chromosome 8p21 is associated with PC susceptibility, which is located at 14 kb downstream of a prostate tumor suppressor gene NKX3.1. To clarify a susceptibility gene and functional variants in this locus, we performed re-sequencing and fine mapping of this region and identified 12 candidates of functional single nucleotide polymorphisms that were absolutely linked with each other. Screening of these variants by RNA stability assay, electrophoretic mobility shift assay (EMSA) and reporter assay indicated that rs11781886 in the 5′-UTR of NKX3.1 displayed different binding affinity to nuclear proteins between the alleles, and that the transcriptional activity of the NKX3.1 promoter was significantly lower in the susceptible allele of this variant. Sp1 was determined to be the transcription factor that binds to the susceptible G allele, but not to the non-susceptible A allele. Allele-specific transcript quantification (ASTQ) and quantitative PCR analyses showed that the expression of NKX3.1 in the prostate was significantly lower in the subjects with the haplotype carrying the susceptible allele. These results suggest that the functional variant rs11781886 in the 5′-UTR of NKX3.1 can affect its transcription by altering the binding affinity of a transcriptional factor Sp1, and might result in PC susceptibility by lowering expression of NKX3.1 in the prostate.

UR - http://www.scopus.com/inward/record.url?scp=77957878164&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957878164&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddq350

DO - 10.1093/hmg/ddq350

M3 - Article

VL - 19

SP - 4265

EP - 4272

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 21

M1 - ddq350

ER -

Akamatsu S, Takata R, Ashikawa K, Hosono N, Kamatani N, Fujioka T et al. A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression. Human molecular genetics. 2010 Aug 17;19(21):4265-4272. ddq350. https://doi.org/10.1093/hmg/ddq350