IRX4 at 5p15 suppresses prostate cancer growth through the interaction with vitamin D receptor, conferring prostate cancer susceptibility.
Recent genome-wide association studies (GWAS) identified a number of prostate cancer (PC) susceptibility loci, but most of their functional significances are not elucidated. Through our previous GWAS for PC in a Japanese population and subsequent resequencing and fine mapping, we here identified that IRX4 (Iroquois homeobox 4), coding Iroquois homeobox 4, is a causative gene of the PC susceptibility locus (rs12653946) at chromosome 5p15. IRX4 is expressed specifically in the prostate and heart, and quantitative expression analysis revealed a significant association between the genotype of rs12653946 and IRX4 expression in normal prostate tissues. Knockdown of IRX4 in PC cells enhanced their growth and IRX4 overexpression in PC cells suppressed their growth, indicating the functional association of IRX4 with PC and its tumor suppressive effect. Immunoprecipitation confirmed its protein-protein interaction to vitamin D receptor (VDR), and we found a significant interaction between IRX4 and VDR in their reciprocal transcriptional regulation. These findings indicate that the PC-susceptibility locus represented by rs12653946 at 5p15 is likely to regulate IRX4 expression in prostate which could suppress PC growth by interacting with the VDR pathway, conferring to PC susceptibility.
Laboratory for Biomarker Development, Center for Genome Medicine, RIKEN, Tokyo, Japan.
Hai Ha
HH
Nguyen
Ryo
R
Takata
Shusuke
S
Akamatsu
Daichi
D
Shigemizu
Tatsuhiko
T
Tsunoda
Mutsuo
M
Furihata
Atsushi
A
Takahashi
Michiaki
M
Kubo
Naoyuki
N
Kamatani
Osamu
O
Ogawa
Tomoaki
T
Fujioka
Yusuke
Y
Nakamura
Hidewaki
H
Nakagawa
D020121:5' Untranslated Regions; D001483:Base Sequence; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D003001:Cloning, Molecular; D005091:Exons; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D018167:Receptors, Calcitriol / Q000378:metabolism*
D020121:5' Untranslated Regions; D018398:Homeodomain Proteins; C485533:IRX4 protein, human; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol