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Antagonistic interaction between androgen signaling and vitamin D signaling in prostate cancer [Expression profiling]

ABSTRACT: Vitamin D induces anti-proliferative and differentiating effects in prostate cancer. Thus calcitriol, the hormonally active form of Vitamin D, and its analogs have been extensively studied in prostate cancer cells. Yet despite its importance, relatively little is known about the genome-scale mechanisms by which Vitamin D, through its cognate nuclear vitamin D receptor (VDR), exerts its regulatory functions at the genomic level. In this study, we defined VDR transcriptional networks in the LNCaP prostate cancer cell line by mapping the genomic binding sites of VDR and by identifying differentially expressed genes upon calcitriol treatment. We found that VDR and androgen receptor (AR) antagonistically regulate a subset of cell cycle-related genes that are over-expressed in prostate cancer tumors. The expression balance of these genes is partially regulated through the competition dynamics between AR and VDR binding to shared cis-regulatory elements. On such shared elements, we found that FOXA1 mediates this competition by serving as a pioneering factor for both AR and VDR binding. We also found significant enrichment of AR-, VDR-, and AR/VDR overlapping binding sites in prostate cancer-associated single-nucleotide polymorphism (SNP) intervals identified from genome-wide association studies (GWAS), providing genetic evidence to link AR, VDR and their crosstalk to prostate cancer susceptibilities. In particular, we found that in a cis-regulatory element of the RFX6 gene implicated in prostate cancer progression, an allelic variant increases prostate cancer risk by switching the antagonism between AR and VDR into a synergistic interaction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60956 | GEO | 2015/08/01

SECONDARY ACCESSION(S): PRJNA259907

REPOSITORIES: GEO

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Project description:Most prostate cancers depend on androgen and androgen receptor signaling for their proliferation and development, which underpins the efficacy of antiandrogens as powerful therapeutic agents for prostate cancers. On the other hand, interaction between AR and other nuclear hormone receptors (NRs) such as glucocorticoid receptor in the prostatic cancer or between AR and ER in breast cancers depicts the close association or “crosstalk” of AR with other NRs in terms of the new approach toward the management of hormone-resistant prostate/breast cancers. Along with this line, chemopreventive and antiproliferative action of 1,25(OH)2D3 (abbreviated as 1,25D3), an active metabolite of vitamin D3, during the management of prostate and/or breast cancers has been recently rigorously argued. We found that in its physiological concentration, 25(OH)D3 (abbreviated as 25D3), the precursor metabolite of 1,25D3 and widely-recognized as an inactive vitamin D because of its much weaker binding activity to vitamin D receptor (VDR) compared to 1,25D3, has a gene transcription profile similar to 1,25D3 in some prostate cancers. In this study, we investigated whole genome target gene profiles and intracellular behaviors of VDR after administration of 25D3 or 1,25D3 in prostate cancer LNCaP cells to elucidate the hormonal activity of 25D3. First, we confirmed that LNCaP cells possessed functional 25D3-VDR as well as 1,25D3-VDR signaling systems by qRT-PCR. By immunofluorescent examination of nuclear translocation, western blotting and most importantly, knockdown of CYP27B1 and/or VDR after the introduction of the respective siRNA into these cells, we found that, just like 1,25D3, 10-7 M of 25D3, which is within its uppermost physiological concentrations in the bloodstream, induced VDR nuclear import and robustly activated its target gene such as CYP24A1 in the virtual absence of CYP27B1 expression in LNCaP cells. These results indicate that the unconverted 25D3 alone behaved similarly to 1,25D3 in activating CYP24A1 mRNA expression. Our comprehensive microarray analyses verified the bioactivity of 25D3 and we found that 25D3 target gene profiles largely matched those of 1,25D3, while the presence a small subset of 25D3-, or 1,25D3-specific target genes were not excluded. The concentration of 1,25D3 in the culture media after 25D3 treatment with or without siRNA for CYP27B1 mRNA was below the lower limit of the sensitivity measured by ultrasensitive LC/MS/MS method. These results indicated that 25D3 shares bioactivity with 1,25D3 without conversion to the latter at least in some prostate cancer cells.

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Antagonistic interaction between androgen signaling and vitamin D signaling in prostate cancer [Expression profiling]

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