Association of a novel long non-coding RNA in 8q24 with prostate cancer susceptibility.
Recent genome-wide association studies reported strong and reproducible associations of multiple genetic variants in a large "gene-desert" region of chromosome 8q24 with susceptibility to prostate cancer (PC). However, the causative or functional variants of these 8q24 loci and their biological mechanisms associated with PC susceptibility remain unclear and should be investigated. Here, focusing on its most centromeric region (so-called Region 2: Chr8: 128.14-128.28 Mb) among the multiple PC loci on 8q24, we performed fine mapping and re-sequencing of this critical region and identified SNPs (single nucleotide polymorphisms) between rs1456315 and rs7463708 (chr8: 128,173,119-128,173,237 bp) to be most significantly associated with PC susceptibility (P = 2.00 × 10(-24) , OR = 1.74, 95% confidence interval = 1.56-1.93). Importantly, we show that this region was transcribed as a ∼13 kb intron-less long non-coding RNA (ncRNA), termed PRNCR1 (prostate cancer non-coding RNA 1), and PRNCR1 expression was upregulated in some of the PC cells as well as precursor lesion prostatic intraepithelial neoplasia. Knockdown of PRNCR1 by siRNA attenuated the viability of PC cells and the transactivation activity of androgen receptor, which indicates that PRNCR1 could be involved in prostate carcinogenesis possibly through androgen receptor activity. These findings could provide a new insight in understanding the pathogenesis of genetic factors for PC susceptibility and prostate carcinogenesis.
Chung
Suyoun
S
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Nakagawa
Hidewaki
H
Uemura
Motohide
M
Piao
Lianhua
L
Ashikawa
Kyota
K
Hosono
Naoya
N
Takata
Ryo
R
Akamatsu
Shusuke
S
Kawaguchi
Takahisa
T
Morizono
Takashi
T
Tsunoda
Tatsuhiko
T
Daigo
Yataro
Y
Matsuda
Koichi
K
Kamatani
Naoyuki
N
Nakamura
Yusuke
Y
Kubo
Michiaki
M
D045744:Cell Line, Tumor; D002470:Cell Survival; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8; D003001:Cloning, Molecular; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D022661:RNA, Untranslated / Q000235:genetics*; D011944:Receptors, Androgen / Q000502:physiology
C410798:AR protein, human; D022661:RNA, Untranslated; D011944:Receptors, Androgen