Identification of novel androgen receptor target genes in prostate cancer

Jariwala, Unnati; Prescott, Jennifer; Li, Jia; Barski, Artem; Pregizer, Steve; Cogan, Jon; Arasheben, Armin; Tilley, Wayne D.; Scher, Howard I.; Gerald, William L.; Buchanan, Grant; Coetzee, Gerhard A.; Frenkel, Baruch

doi:10.1186/1476-4598-6-39

Cited by 94 publications

(66 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the ARBSs are also relatively evenly distributed at distal enhancer regions within 25kb up or downstream of the TSS. This result is in agreement with several other reports that ARBSs are not limited to the proximal promoter immediately upstream of the transcriptional start sites (Jariwala, et al, 2007; Takayama, et al, 2007; Waltering, et al, 2009; Wang, et al, 2007). …”

Section: Resultssupporting

confidence: 94%

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

Narisu

Schlick

et al. 2015

Human Mutation

View full text Add to dashboard Cite

Genome-wide association studies have identified genomic loci, whose single nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the mechanisms of most of these variants are largely unknown. We integrated chromatin-IP coupled sequencing and microarray expression profiling in TMPRSS2-ERG gene rearrangement positive DUCaP cells with the GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Among the 48 GWAS index risk SNPs and 3,917 linked SNPs, 80 were found located in ARBSs. Of these, rs11891426:T>G in an intron of the melanophilin gene (MLPH), was within a novel putative auxiliary AR binding motif, which is enriched in the neighborhood of canonical androgen responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay. The expression of melanophilin in primary prostate tumors was significantly lower in those with the G compared to the T allele and correlated significantly with AR protein. Higher melanophilin level in prostate tissue of patients with a favourable PCa risk profile points out a tumor suppressive effect. These results unravel a hidden link between AR and a functional putative PCa risk SNP, whose allele alteration affects androgen regulation of its host gene MLPH.

show abstract

Section: Resultssupporting

confidence: 94%

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

Narisu

Schlick

et al. 2015

Human Mutation

View full text Add to dashboard Cite

show abstract

“…Thus, enhanced TRPV3 function can indeed explain the allergic and inflammatory manifestations displayed by the affected skin tissues of the mutant rodents. Furthermore, a recent study has identified TRPV3 as a novel target of androgen receptors that displays enhanced expression in response to dihydrotestosterone [25], suggestive a potential link of TRPV3 upregulation in androgenetic alopecia, a common problem that affects approximately 50% of the male population.…”

Section: Discussionmentioning

confidence: 99%

The TRPV3 mutation associated with the hairless phenotype in rodents is constitutively active

Xiao¹,

Tian²,

Tang³

et al. 2008

Cell Calcium

View full text Add to dashboard Cite

SummaryTRPV3 is a non-selective cation channel activated by warm to hot temperatures. In rodents, TRPV3 is highly expressed in basal keratinocytes of skin and oral/nasal epithelia. TRPV3 knockout mice showed impaired responses to innocuous and noxious heat but otherwise normal appearance and reactions to many sensory modalities. However, point mutations of TRPV3 at Gly573 to Ser and Cys have recently been linked to autosomal dominant hairless phenotypes and spontaneous dermatitis in mice and rats, implicating an important role for TRPV3 in alopecia and skin diseases. Exactly how the mutations affect TRPV3 function was unexplained. Here we show that both G573S and G573C mutations of murine TRPV3 are constitutively active in heterologous systems. In HEK293 cells, expression of the TRPV3 mutants causes cell death. In Xenopus oocytes, the constitutively active mutant channel is irresponsive to thermal and chemical stimuli but it reduces the temperature threshold and enhances the responses to heat and TRPV3 agonists of the wild type channel when they are co-expressed. We conclude that the G573S and G573C substitutions render the TRPV3 channel spontaneously active under normal physiological conditions, which in turn alters ion homeostasis and membrane potentials of skin keratinocytes, leading to hair loss and dermatitis-like skin diseases.

show abstract

“…Androgens are critical to the normal development, proliferation, and differentiation of prostate epithelial cells and signaling occurs via intracellular AR [23,32]. Recurrent prostate cancer after primary treatment is typically androgen-dependent, and so androgen deprivation therapy is effective in causing a remission of prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor

Hong

Seeram

Heber

2008

The Journal of Nutritional Biochemistry

135

View full text Add to dashboard Cite

Prostate cancer is dependent on circulating testosterone in its early stages and is treatable with radiation and surgery. However, recurrent prostate tumors advance to an androgen-independent state where they progress in the absence of circulating testosterone leading to metastasis and death. During the development of androgen independence, prostate cancer cells are known to increase intracellular testosterone synthesis which maintains cancer cell growth in the absence of significant amounts of circulating testosterone. Overexpression of the androgen receptor (AR) occurs in androgenindependent prostate cancer and has been proposed as another mechanism promoting the development of androgen independence. The LNCaP-AR cell line is engineered to overexpress AR but is otherwise similar to the widely studied LNCaP cell line. We have previously shown that pomegranate extracts inhibit both androgen-dependent and androgen-independent prostate cancer cell growth. In the present study, we examined the effects of pomegranate polyphenols, ellagitanninrich extract and whole juice extract on the expression of genes for key androgen synthesizing enzymes and the AR. We measured expression of the HSD3B2, AKR1C3 and SRD5A1 genes for the respective androgen synthesizing enzymes in LNCaP, LNCaP-AR, and DU-145 human prostate cancer cells. A two-fold suppression of gene expression was considered statistically significant. Pomegranate polyphenols inhibited gene expression and AR most consistently in the LNCaP-AR cell line (P =.05). Therefore, inhibition by pomegranate polyphenols of gene expression involved in androgen synthesis enzymes and the AR may be of particular importance in androgen-independent prostate cancer cells and the subset of human prostate cancers where AR is upregulated.

show abstract

Identification of novel androgen receptor target genes in prostate cancer

Abstract: Background: The androgen receptor (AR) plays critical roles in both androgen-dependent and castrate-resistant prostate cancer (PCa). However, little is known about AR target genes that mediate the receptor's roles in disease progression.

Cited by 94 publications

References 68 publications

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

The TRPV3 mutation associated with the hairless phenotype in rodents is constitutively active

Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor

Contact Info

Product

Resources

About