Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Discovery of novel hypermethylated gene loci in prostate cancer using genome wide coverage CpG island microarrays

ABSTRACT: In order to identify methylation changes in prostate cancer, we performed a genome-wide analysis of DNA methylation using Agilent human CpG island arrays. We then chose specific genes to validate methylation both in the same cases as were hybridized to the array (using quantitative EpiTYPER analysis) and in an independent series of prostate cancer samples (using MethyLight quantitative methylation specific PCR). We specifically chose low grade (Gleason score 6 cases) and high grade (Gleason score 8 cases) to discover methylated genes/loci that may be involved in the progression to a higher grade of prostate cancer. We collected 20 specimens consisting of 10 Gleason 6 and 10 Gleason 8 prostate cancers, and compared these to a reference lymphocyte pool (6 age matched, healthy men) to determine cancer associated methylation changes as well as disease progression associated methylation changes. We performed the differential methylation hybridization procedure as described by Yan et al. (Methods, 2002) on each case to enrich for methylated DNA. Each specimen in the reference pool underwent the same enrichment with amplicons being pooled at the end of the procedure. Each prostate cancer case was subsequently co-hybridized to the microarray with the reference pool.

ORGANISM(S): Homo sapiens

SUBMITTER: Ken Kron

PROVIDER: E-GEOD-15298 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Discovery of novel hypermethylated genes in prostate cancer using genomic CpG island microarrays.

Kron Ken K Pethe Vaijayanti V Briollais Laurent L Sadikovic Bekim B Ozcelik Hilmi H Sunderji Alia A Venkateswaran Vasundara V Pinthus Jehonathan J Fleshner Neil N van der Kwast Theodorus T Bapat Bharati B

PloS one 20090313 3

<h4>Background</h4>Promoter and 5' end methylation regulation of tumour suppressor genes is a common feature of many cancers. Such occurrences often lead to the silencing of these key genes and thus they may contribute to the development of cancer, including prostate cancer.<h4>Methodology/principal findings</h4>In order to identify methylation changes in prostate cancer, we performed a genome-wide analysis of DNA methylation using Agilent human CpG island arrays. Using computational and gene-sp ...[more]

PMID: 19283074

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Project description:The androgen receptor (AR) plays a key role in progression to incurable androgen-ablation resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand binding domain (designated as AR3, AR4 and AR5) in hormone insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly upregulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells while specific knock-down of AR3 expression (without altering AR level) in hormone resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct yet essential role in ablation-independent growth through regulating a unique set of genes including AKT1, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation-independence during PCA progression and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available anti-androgen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA. Total RNA was extracted from CWR-R1 and 22Rv1 cells treated with shAR3-1, shARa and the scrambled shRNA control, respectively. Each of CWR-R1 and 22Rv1 cells treated with shAR3-1 was compared with the scrambled shRNA control. The same experiments were performed for the cells treated with shARa.

Dataset Information

Discovery of novel hypermethylated gene loci in prostate cancer using genome wide coverage CpG island microarrays

Publications

Discovery of novel hypermethylated genes in prostate cancer using genomic CpG island microarrays.

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