IRX4 at 5p15 suppresses prostate cancer growth through the interaction with vitamin D receptor, conferring prostate cancer susceptibility

Hai Ha Nguyen, Ryo Takata, Shusuke Akamatsu, Daichi Shigemizu, Tatsuhiko Tsunoda, Mutsuo Furihata, Atsushi Takahashi, Michiaki Kubo, Naoyuki Kamatani, Osamu Ogawa, Tomoaki Fujioka, Yusuke Nakamura, Hidewaki Nakagawa

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article numberdds025
Pages (from-to)2076-2085
Number of pages10
JournalHuman molecular genetics
Volume21
Issue number9
DOIs
Publication statusPublished - 01-05-2012

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Calcitriol Receptors
Homeobox Genes
Prostatic Neoplasms
Growth
Prostate
Genome-Wide Association Study
Immunoprecipitation
Proteins
Chromosomes
Genotype

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Nguyen, H. H., Takata, R., Akamatsu, S., Shigemizu, D., Tsunoda, T., Furihata, M., ... Nakagawa, H. (2012). IRX4 at 5p15 suppresses prostate cancer growth through the interaction with vitamin D receptor, conferring prostate cancer susceptibility. Human molecular genetics, 21(9), 2076-2085. [dds025]. https://doi.org/10.1093/hmg/dds025
Nguyen, Hai Ha ; Takata, Ryo ; Akamatsu, Shusuke ; Shigemizu, Daichi ; Tsunoda, Tatsuhiko ; Furihata, Mutsuo ; Takahashi, Atsushi ; Kubo, Michiaki ; Kamatani, Naoyuki ; Ogawa, Osamu ; Fujioka, Tomoaki ; Nakamura, Yusuke ; Nakagawa, Hidewaki. / IRX4 at 5p15 suppresses prostate cancer growth through the interaction with vitamin D receptor, conferring prostate cancer susceptibility. In: Human molecular genetics. 2012 ; Vol. 21, No. 9. pp. 2076-2085.
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abstract = "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.",
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Nguyen, HH, Takata, R, Akamatsu, S, Shigemizu, D, Tsunoda, T, Furihata, M, Takahashi, A, Kubo, M, Kamatani, N, Ogawa, O, Fujioka, T, Nakamura, Y & Nakagawa, H 2012, 'IRX4 at 5p15 suppresses prostate cancer growth through the interaction with vitamin D receptor, conferring prostate cancer susceptibility', Human molecular genetics, vol. 21, no. 9, dds025, pp. 2076-2085. https://doi.org/10.1093/hmg/dds025

IRX4 at 5p15 suppresses prostate cancer growth through the interaction with vitamin D receptor, conferring prostate cancer susceptibility. / Nguyen, Hai Ha; Takata, Ryo; Akamatsu, Shusuke; Shigemizu, Daichi; Tsunoda, Tatsuhiko; Furihata, Mutsuo; Takahashi, Atsushi; Kubo, Michiaki; Kamatani, Naoyuki; Ogawa, Osamu; Fujioka, Tomoaki; Nakamura, Yusuke; Nakagawa, Hidewaki.

In: Human molecular genetics, Vol. 21, No. 9, dds025, 01.05.2012, p. 2076-2085.

Research output: Contribution to journalArticle

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T1 - IRX4 at 5p15 suppresses prostate cancer growth through the interaction with vitamin D receptor, conferring prostate cancer susceptibility

AU - Nguyen, Hai Ha

AU - Takata, Ryo

AU - Akamatsu, Shusuke

AU - Shigemizu, Daichi

AU - Tsunoda, Tatsuhiko

AU - Furihata, Mutsuo

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Kamatani, Naoyuki

AU - Ogawa, Osamu

AU - Fujioka, Tomoaki

AU - Nakamura, Yusuke

AU - Nakagawa, Hidewaki

PY - 2012/5/1

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N2 - 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.

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