251: Transcriptomes of Human Prostate Cells

Oudes, Asa; Campbell, Dave S; Walashek, Laura S; Sorensen, Carrie M.; True, Lawrence D.; Liu, Alvin Y.

doi:10.1016/s0022-5347(18)32518-7

Cited by 13 publications

(17 citation statements)

References 10 publications

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“…We named these genes 'Differentiation-Associated Hypermethylated' (DAH). Expression analysis of DAH genes in the same data sets 35,36 revealed that they are strongly enriched for genes downregulated in CaP tissues, and also in normal luminal cells (Figures 3b and c), supporting the hypothesis that these genes are, like GSTP1, mainly downregulated during differentiation and subsequently hypermethylated in CaP.…”

Section: Resultssupporting

confidence: 66%

“…genes hypermethylated in CaP. We generated a comprehensive list of promoters hypermethylated in CaP from publicly available resources and assessed gene expression in three data sets: CaP versus normal prostate tissues, 35 luminal versus basal primary prostate cells, 36 CaP versus BPHderived basal cells. 29 As expected, 'genes hypermethylated in We then generated a list of genes highly expressed in prostate basal cells from BPH and CaP 29 and intersected it with the list of genes hypermethylated in CaP, finding 206 genes that are potentially regulated similarly to GSTP1 (Figure 3a and Supplementary Table 1).…”

Section: Resultsmentioning

confidence: 99%

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DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation

et al. 2014

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Prostate cancer (CaP) is mostly composed of luminal-like differentiated cells, but contains a small subpopulation of basal cells (including stem-like cells), which can proliferate and differentiate into luminal-like cells. In cancers, CpG island hypermethylation has been associated with gene downregulation, but the causal relationship between the two phenomena is still debated. Here we clarify the origin and function of CpG island hypermethylation in CaP, in the context of a cancer cell hierarchy and epithelial differentiation, by analysis of separated basal and luminal cells from cancers. For a set of genes (including GSTP1) that are hypermethylated in CaP, gene downregulation is the result of cell differentiation and is not cancer specific. Hypermethylation is however seen in more differentiated cancer cells and is promoted by hyperproliferation. These genes are maintained as actively expressed and methylation-free in undifferentiated CaP cells, and their hypermethylation is not essential for either tumour development or expansion. We present evidence for the causes and the dynamics of CpG island hypermethylation in CaP, showing that, for a specific set of genes, promoter methylation is downstream of gene downregulation and is not a driver of gene repression, while gene repression is a result of tissue-specific differentiation.

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Section: Resultssupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation

et al. 2014

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“…Another report using the same antiserum also showed a similar immunohistochemical staining pattern (27). To identify which populations of prostatic cells expressed AKR1C1 and AKR1C2, transcriptome analysis of four highly enriched populations of luminal, basal, stromal, and endothelial cells from the prostate was queried using the SCGAP Urologic Epithelial Stem Cells Project web site 5 (28). Relative expression profile from the most abundant to least revealed the following expression patterns: AKR1C1, stromal, luminal > endothelial >> basal; AKR1C2, stromal, luminal > endothelial > basal; and AKR1C3, basal, endothelial > stromal > luminal cells.…”

Section: Resultsmentioning

confidence: 99%

Impaired Dihydrotestosterone Catabolism in Human Prostate Cancer: Critical Role of AKR1C2 as a Pre-Receptor Regulator of Androgen Receptor Signaling

Chang

Stanczyk

et al. 2007

Cancer Research

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We previously reported the selective loss of AKR1C2 and AKR1C1 in prostate cancers compared with their expression in paired benign tissues. We now report that dihydrotestosterone (DHT) levels are significantly greater in prostate cancer tumors compared with their paired benign tissues. Decreased catabolism seems to account for the increased DHT levels as expression of AKR1C2 and SRD5A2 was reduced in these tumors compared with their paired benign tissues. After 4 h of incubation with benign tissue samples, 3 H-DHT was predominately catabolized to the 5A-androstane-3A,17B-diol metabolite. Reduced capacity to metabolize DHT was observed in tumor samples from four of five freshly isolated pairs of tissue samples, which paralleled loss of AKR1C2 and AKR1C1 expression. LAPC-4 cells transiently transfected with AKR1C1 and AKR1C2, but not AKR1C3, were able to significantly inhibit a dose-dependent, DHT-stimulated proliferation, which was associated with a significant reduction in the concentration of DHT remaining in the media. R1881-stimulated proliferation was equivalent in all transfected cells, showing that metabolism of DHT was responsible for the inhibition of proliferation. PC-3 cells overexpressing AKR1C2 and, to a lesser extent, AKR1C1 were able to significantly inhibit DHT-dependent androgen receptor reporter activity, which was abrogated by increasing DHT levels. We speculate that selective loss of AKR1C2 in prostate cancer promotes clonal expansion of tumor cells by enhancement of androgen-dependent cellular proliferation by reducing DHT metabolism. [Cancer Res 2007;67(3):1361-9]

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“…This qualifies antibacterial peptides such as defensins as candidates for an important role also in cancer development and manifestation. Thereby defensins may be expressed in prostate tissue [36] and/or immunocompetent cells [7] attracted to the sites of tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants of the Copy Number Polymorphic β-Defensin Locus Are Associated with Sporadic Prostate Cancer

Huse¹,

Taudien²,

Groth³

et al. 2008

Tumor Biol

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Background/Aims: Prostate cancer represents the cancer with the highest worldwide prevalence in men. Chromosome 8p23 has shown suggestive genetic linkage to early-onset familial prostate cancer and is frequently deleted in cancer cells of the urogenital tract. Within this locus some β-defensin genes (among them DEFB4, DEFB103, DEFB104) are localized, which are arranged in a gene cluster shown to exhibit an extensive copy number variation in the population. This structural variation considerably hampers genetic studies. In a new approach considering both sequence as well as copy number variations we aimed to compare the defensin locus at 8p23 in prostate cancer patients and controls. Methods: We apply PCR/cloning-based haplotyping and high-throughput copy number determination methods which allow assessment of both individual haplotypes and gene copy numbers not accessible to conventional SNP-based genotyping. Results: We demonstrate association of four common DEFB104 haplotypes with the risk of prostate cancer in two independent patient cohorts. Moreover, we show that high copy numbers (>9) of the defensin gene cluster are significantly underrepresented in both patient samples. Conclusions: Our findings imply a role of the antibacterial defensins in prostate cancerogenesis qualifying distinct gene variants and copy numbers as potential tumor markers.

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251: Transcriptomes of Human Prostate Cells

Cited by 13 publications

References 10 publications

DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation

DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation

Impaired Dihydrotestosterone Catabolism in Human Prostate Cancer: Critical Role of AKR1C2 as a Pre-Receptor Regulator of Androgen Receptor Signaling

Genetic Variants of the Copy Number Polymorphic β-Defensin Locus Are Associated with Sporadic Prostate Cancer

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251: Transcriptomes of Human Prostate Cells

Cited by 13 publications

References 10 publications

DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation

DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation

Impaired Dihydrotestosterone Catabolism in Human Prostate Cancer: Critical Role of AKR1C2 as a Pre-Receptor Regulator of Androgen Receptor Signaling

Genetic Variants of the Copy Number Polymorphic &beta;-Defensin Locus Are Associated with Sporadic Prostate Cancer

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Genetic Variants of the Copy Number Polymorphic β-Defensin Locus Are Associated with Sporadic Prostate Cancer