BERKELEY, CA (UroToday.com) - It is clearly evident that genetic factors play some important roles in prostate cancer etiology.
Recent genome-wide association studies (GWAS) which analyzed 50-100 thousands of genetic variants in the human genome have identified more than 50 single nucleotide polymorphisms (SNP) on various genes or chromosome loci which are associated to PC susceptibility. However, most of their functional significances in prostate carcinogenesis are not elucidated because more than a half of these prostate cancer-associated SNPs or genetic variants are located in non-coding regions (not coding proteins) in human genome.
| "...further functional analysis on these genes or variants will better clarify the molecular mechanism of prostate carcinogenesis, leading to improvement of prostate cancer treatment and diagnosis." |
In this study, we focused on one SNP at chromosome 5p15 (rs12653946) which was recently identified as one of the prostate cancer-associated SNPs by our prostate cancer GWAS in Japanese population (Takata et al.Nature Genetics 42: 751-754, 2010) and its association with prostate cancer was also replicated in other populations, and we investigated into how this genetic variant was related with molecular biology of prostate cancer. We demonstrated that IRX4 is a causative gene of this prostate cancer susceptibility locus at chromosome 5p15 and this genetic variant could regulate IRX4 expression in prostate. IRX4 (Iroquois homeobox 4) is a member of the Iroquois family of homeobox transcription factors that plays as an important mediator of heart differentiation during cardiac development. But IRX4 is also expressed specifically in the prostate as well as in the heart, and knockdown of IRX4 in prostate cancer cells enhanced their growth and IRX4 overexpression in prostate cancer cells suppressed their growth, indicating that IRX4 is likely to have some tumor suppressive effects in prostate.
We also demonstrated that IRX4 protein could bind directly with Vitamin D receptor (VDR), and we found a significant interaction between IRX4 and VDR in their reciprocal transcriptional regulation. Vitamin D and VDR exert anti-proliferation and anti-differentiation effect in prostate cancer and other cancers, and this pathway is a target for chemoprevention or chemotherapy of prostate cancer, although the molecular mechanism of the tumor suppressive effect of VDR pathway is still unclear. This functional interaction of a novel prostate cancer gene IRX4 and VDR could shed light on the mechanism of anti-proliferation effect of vitamin D and VDR pathway on prostate cancer development and progression, and IRX4-VDR pathway may be a promising molecular target for diagnosis and prevention of prostate cancer. Now this genetic approach to study prostate cancer genomics (GWAS) has been successful to identify many novel genes or variants associated with prostate cancer, and further functional analysis on these genes or variants will better clarify the molecular mechanism of prostate carcinogenesis, leading to improvement of prostate cancer treatment and diagnosis.
Written by:
Hidewaki Nakagawa, MD, PhD* as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
*RIKEN Center for Genomic Medicine
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