Integrative Epigenome Map of the Normal Human Prostate Provides Insights Into Prostate Cancer Predisposition

Cells of all tissues in the human body share almost the exact same DNA sequence, but the epigenomic landscape can be drastically distinct. To improve our understanding of the epigenetic abnormalities in prostate-related diseases, it is important to use the epigenome of normal prostate as a reference. Although previous efforts have provided critical insights into the genetic and transcriptomic features of the normal prostate, a comprehensive epigenome map has been lacking. To address this need, we conducted a Roadmap Epigenomics legacy project integrating six histone marks (H3K4me1, H3K4me3, H3K9me3, H3K36me3, H3K27me3, and H3K27ac) with complete DNA methylome, transcriptome, and chromatin accessibility data to produce a comprehensive epigenome map of normal prostate tissue. Our epigenome map is composed of 18 chromatin states each with unique signatures of DNA methylation, chromatin accessibility, and gene expression. This map provides a high-resolution comprehensive annotation of regulatory regions of the prostate, including 105,593 enhancer and 70,481 promoter elements, which account for 5.3% of the genome. By comparing with other epigenomes, we identified 7,580 prostate-specific active enhancers associated with prostate development. Epigenomic annotation of GWAS SNPs associated with prostate cancers revealed that two out of nine SNPs within prostate enhancer regions destroyed putative androgen receptor (AR) binding motif. A notable SNP rs17694493, might decouple AR’s repressive effect on CDKN2B-AS1 and cell cycle regulation, thereby playing a causal role in predisposing cancer risk. The comprehensive epigenome map of the prostate is valuable for investigating prostate-related diseases.

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Epithelial Phenotypes in the Developing Human Prostate

Journal of Histochemistry & Cytochemistry ◽

10.1369/jhc.7a7192.2007 ◽

2007 ◽

Vol 55 (9) ◽

pp. 885-890 ◽

Cited By ~ 8

Author(s):

Guy Letellier ◽

Marie-José Perez ◽

Mokrane Yacoub ◽

Pierre Levillain ◽

Olivier Cussenot ◽

...

Keyword(s):

Androgen Receptor ◽

Growth Factor ◽

Regulatory Function ◽

Basal Cells ◽

Normal Prostate ◽

Prostate Development ◽

Proliferation And Apoptosis ◽

Normal Prostate Tissue ◽

Epidermal Growth ◽

Luminal Cells

An intermediate population has been identified among prostate glands called transiently amplifying (TA) cells, which are characterized by coexpression of basal and luminal cytokeratins (CKs), high proliferation, and lack of p27 expression. These cells are rare in the normal adult prostate and increase in pretumoral conditions, but their importance in the developing gland remains unknown. We analyzed fetal prostates for the expression of CKs (5/6, 18, 19) and factors involved in proliferation and apoptosis: p63, Ki67, p27, epidermal growth factor (EGFR), Bcl2, androgen receptor (AR). Immunostaining was performed on a tissue microarray, including 40 prostates from fetuses aged 13-42 weeks and normal prostate tissue from 10 adults. In both solid buds and the basal compartment of canalized glands, cells expressed p63, CK5/6, CK19, CK18, BCL2, EGFR and were p27 negative. Luminal cells of fetal canalized glands continue to express CK19, EGFR, and BCL2, without p27 expression. In contrast, adult epithelial luminal cells showed diffuse AR and p27 expression, without CK19, BCL2, and EGFR staining. Proliferation was high and diffuse in fetal glands and rare and restricted to basal cells in adult glands. These results indicate that most fetal epithelial prostatic cells exhibit the phenotype of TA cells, suggesting their regulatory function in prostate development.

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EXPRESSION OF CANCER-ASSOCIATED GENES IN PROSTATE TUMORS

Experimental Oncology ◽

10.31768/2312-8852.2017.39(2):131-137 ◽

2017 ◽

Vol 39 (2) ◽

pp. 131-137 ◽

Cited By ~ 6

Author(s):

E E Rosenberg ◽

G V Gerashchenko ◽

N V Hryshchenko ◽

L V Mevs ◽

K A Nekrasov ◽

...

Keyword(s):

Prostate Cancer ◽

Prostate Tumors ◽

Normal Prostate ◽

Expression Levels ◽

Relative Expression ◽

Normal Tissues ◽

Prostate Cancer Development ◽

Normal Prostate Tissue ◽

Significant Expression ◽

Prostate Cancers

Background: Prostate cancer is one of the most common male cancers in Western countries and takes the third place in morbidity in Ukraine. It is a highly heterogeneous disease. Aim: To analyze relative expression levels of the TGFB1, IL1B, FOS, EFNA5, TAGLN, PLAU, and EPDR1 genes in malignant and non-malignant prostate tissues. Materials and Methods: Total RNA was isolated from 16 prostate adenomas, 37 prostate adenocarcinomas, and 29 conventionally normal prostate tissues. To analyze relative gene expression levels the quantitative real-time polymerase chain reaction was performed. Results: The significant alterations in the relative expression levels were found in all analyzed sample groups for 4 genes: FOS, EFNA5, IL1B, and TGFB1. We have found that FOS and EFNA5 were more frequently overexpressed in carcinomas with Gleason score ≤ 7, compared with adenomas. On contrary, PLAU expression levels were decreased more frequently in prostate cancers, compared with conventionally normal tissues. Noteworthy, we found positive correlation between IL1B expression level and PSA (for patients with slight PSA increase, no more than 20.0 ng/ml). Conclusion: The EFNA5, FOS, IL1B, PLAU, and TGFB1 genes that showed significant expression alterations in prostate tumors, compared with conventionally normal prostate tissue, may play role in prostate cancer development and should be further investigated.

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Pyruvate kinase M1 suppresses development and progression of prostate adenocarcinoma

10.1101/2021.05.09.443334 ◽

2021 ◽

Author(s):

Shawn M Davidson ◽

Julia E. Heyman ◽

James P O'Brien ◽

Amy C. Liu ◽

Daniel R. Schmidt ◽

...

Keyword(s):

Prostate Cancer ◽

Pyruvate Kinase ◽

Normal Prostate ◽

Pten Loss ◽

Conditional Allele ◽

Normal Prostate Tissue ◽

Splice Isoform ◽

Isoform Expression ◽

Prostate Cancers

Most cancers, including prostate cancers, express the M2 splice isoform of pyruvate kinase (Pkm2). This isoform can promote anabolic metabolism to support cell proliferation; however, Pkm2 expression is dispensable for many cancers in vivo. Pyruvate kinase M1 (Pkm1) isoform expression is restricted to relatively few tissues and has been reported to promote growth of select tumors, but the role of PKM1 in cancer has been less studied. Pkm1 is expressed in normal prostate tissue; thus, to test how differential pyruvate kinase isoform expression affects cancer initiation and progression we generated mice harboring a conditional allele of Pkm1 and crossed this allele, as well as a Pkm2 conditional allele, to a Pten loss-driven prostate cancer model. We found that Pkm1 loss leads to Pkm2 expression and accelerates prostate cancer, while deletion of Pkm2 leads to increased Pkm1 expression and suppresses cancer. Consistent with these data, a small molecule pyruvate kinase activator that mimics a PKM1-like state suppresses progression of established prostate tumors. PKM2 expression is retained in most human prostate cancers, arguing that pharmacological PKM2 activation may be beneficial for some prostate cancer patients.

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MiR-323 Inhibits Prostate Cancer Vascularization Through Adiponectin Receptor

Cellular Physiology and Biochemistry ◽

10.1159/000430313 ◽

2015 ◽

Vol 36 (4) ◽

pp. 1491-1498 ◽

Cited By ~ 17

Author(s):

Qiruo Gao ◽

Xudong Yao ◽

Junhua Zheng

Keyword(s):

Umbilical Vein ◽

Collagen Gel ◽

Adiponectin Receptor ◽

Luciferase Reporter ◽

Normal Prostate ◽

Vessel Formation ◽

Protein Levels ◽

Normal Prostate Tissue ◽

Prostate Cancers ◽

Umbilical Vein Endothelial Cells

Background/Aims: The current treatments fail to provide satisfactory cure for aggressive prostate cancers (PCs). Hence, further comprehension of PC metastasis is highly appreciated for improving the levels of therapy. We have previously shown that Adiponectin reduces the levels of vascular endothelial growth factor A (VEGF-A) in PCs to suppress tumor-associated neovascularization, possibly through AMPK/mTor signaling. Here, we studied the regulation of Adiponectin signaling in PCs. Methods: We analyzed the levels and correlation of Adiponectin receptor 1 (AdipoR1) and microRNA-323 (miR-323) in the PC specimen, compared to the paired normal prostate tissue. We analyzed the binding of miR-323 to the 3'UTR of AdipoR1 mRNA and its effects on AdipoR1 translation by bioinformatics analysis and by luciferase-reporter assay, respectively. We modified miR-323 levels in PC cells, and examined the effects on the expression of AdipoR1 and VEGF-A, as well as on vessel formation in a human umbilical vein endothelial cells (HUVECs) transwell collagen gel assay. Results: We detected significantly lower levels of AdipoR1 and significantly higher levels of miR-323 in PC specimen. Moreover, the levels of AdipoR1 and miR-323 are inversely correlated. Moreover, miR-323 was found to bind to the 3'UTR of AdipoR1 mRNA to inhibit its translation. Overexpression of miR-323 in PC cells decreased AdipoR1 protein levels, whereas inhibition of miR-323 increased AdipoR1 protein levels, without affecting AdipoR1 transcripts. Moreover, overexpression of miR-323 increased the levels of VEGF-A and the vessel formation by HUVECs, while inhibition of miR-323 decreased the levels of VEGF-A and the vessel formation by HUVECs. Conclusion: Our data demonstrate that miR-323 may increase VEGF-A-mediated cancer vascularization in PC cells through AdipoR1 suppression.

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Faculty Opinions recommendation of Identification of candidate genes for prostate cancer-risk SNPs utilizing a normal prostate tissue eQTL data set.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725966457.793519610 ◽

2016 ◽

Author(s):

Charlotte Bevan ◽

Greg Brooke

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Candidate Genes ◽

Prostate Cancer Risk ◽

Prostate Tissue ◽

Data Set ◽

Normal Prostate ◽

Risk Snps ◽

Normal Prostate Tissue ◽

Eqtl Data

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HERV-K Gag RNA and Protein Levels Are Elevated in Malignant Regions of the Prostate in Males with Prostate Cancer

Viruses ◽

10.3390/v13030449 ◽

2021 ◽

Vol 13 (3) ◽

pp. 449

Author(s):

Simin D. Rezaei ◽

Joshua A. Hayward ◽

Sam Norden ◽

John Pedersen ◽

John Mills ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Lines ◽

Endogenous Retrovirus ◽

Human Endogenous Retrovirus ◽

Normal Prostate ◽

Tissue Samples ◽

Gag Protein ◽

Protein Levels ◽

Prostate Epithelial Cells ◽

Prostate Cancers

Heightened expression of human endogenous retrovirus (HERV) sequences has been associated with a range of malignancies, including prostate cancer, suggesting that they may serve as useful diagnostic or prognostic cancer biomarkers. We analysed the expression of HERV-K (Gag and Env/Np9 regions), HERV-E 4.1 (Pol and Env regions), HERV-H (Pol) and HERV-W (Gag) sequences in prostate cancer cells lines and normal prostate epithelial cells using qRT-PCR. HERV expression was also analysed in matched malignant and benign prostate tissue samples from men with prostate cancer (n = 27, median age 65.2 years (range 47–70)) and compared to prostate cancer-free male controls (n = 11). Prostate cancer epithelial cell lines exhibited a signature of HERV RNA overexpression, with all HERVs analysed, except HERV-E Pol, showing heightened expression in at least two, but more commonly all, cell lines analysed. Analysis of primary prostate material indicated increased expression of HERV-E Pol but decreased expression of HERV-E Env in both malignant and benign regions of the prostate in men with prostate cancer as compared to those without. Expression of HERV-K Gag was significantly higher in malignant regions of the prostate in men with prostate cancer as compared to matched benign regions and prostate cancer-free men (p < 0.001 for both), with 85.2% of prostate cancers donors showing malignancy-associated upregulation of HERV-K Gag RNA. HERV-K Gag protein was detected in 12/18 (66.7%) malignant tissues using immunohistochemistry, but only 1/18 (5.6%) benign tissue sections. Heightened expression of HERV-K Gag RNA and protein appears to be a sensitive and specific biomarker of prostate malignancy in this cohort of men with prostate carcinoma, supporting its potential utility as a non-invasive, adjunct clinical biomarker.

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