Epigenetic Regulation in Prostate Cancer Progression

Ruggero, Katia; Farran-Matas, Sonia; Martínez-Tébar, Adrián; Aytés, Álvaro

doi:10.1007/s40610-018-0095-9

Cited by 56 publications

(66 citation statements)

References 150 publications

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“…By integrating chromatin structural information and transcriptomic data, gene expression patterns have been found to correlate with genes proximal to open chromatin and negatively correlate with TSS methylation in BPH, primary PCs and CRPC specimens . The consistency of these correlations across different disease stages is supportive of other studies showing occurrence of epigenetic deregulation both during tumor initiation and progression to therapy resistance (Perry et al 2010, Ruggero et al 2018.…”

Section: Introductionsupporting

confidence: 85%

“…Interestingly, consequences of activation or reactivation of TFs have been extensively studied with the Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) in the induction of pluripotent stem cells from adult human fibroblasts, and it is apt that this process is associated with considerable epigenetic reprogramming (Takahashi et al 2007, Schmidt & Plath 2012. The role of these TFs in PC have been reviewed in Ruggero et al (2018). In PC, reprogramming of normal human epithelial prostate tissue to a lethal neuroendocrine cancer lineage has proven successful by forcing the expression of TFs such as c-MYC or N-MYC in combination with myristoylated AKT1 (a partial mimic of PTEN loss) (Park et al 2018).…”

Section: The Androgen Receptor Drives Chromatin Relaxation As An Oncomentioning

confidence: 99%

“…As the chromatin structure dictates the accessibility of the genome, it allows cell-type-specific transcription. Unsurprisingly, chromatin structure regulation contributes greatly to cell differentiation and preservation of cell identity, and chromatin deregulation is associated with many diseases, including PC (Ruggero et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

Braadland

Urbanucci

2019

Endocrine-Related Cancer

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Tumor evolution is based on the ability to constantly mutate and activate different pathways under the selective pressure of targeted therapies. Epigenetic alterations including those of the chromatin structure are associated with tumor initiation, progression and drug resistance. Many cancers, including prostate cancer, present enlarged nuclei, and chromatin appears altered and irregular. These phenotypic changes are likely to result from epigenetic dysregulation. High-throughput sequencing applied to bulk samples and now to single cells has made it possible to study these processes in unprecedented detail. It is therefore timely to review the impact of chromatin relaxation and increased DNA accessibility on prostate cancer growth and drug resistance, and their effects on gene expression. In particular, we focus on the contribution of chromatinassociated proteins such as the bromodomain-containing proteins to chromatin relaxation. We discuss the consequence of this for androgen receptor transcriptional activity and briefly summarize wider gain-of-function effects on other oncogenic transcription factors and implications for more effective prostate cancer treatment.

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Section: Introductionsupporting

confidence: 85%

Section: The Androgen Receptor Drives Chromatin Relaxation As An Oncomentioning

confidence: 99%

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Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

Braadland

Urbanucci

2019

Endocrine-Related Cancer

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“…In contrast to other genomic abnormalities, cancer-specific DNA methylation alterations are highly prevalent in prostate cancer, making them a sustained focus of research, [14][15][16][17][18][19][20][21][22][23][24][25] with growing evidence supporting their role in progression and risk stratification. [26][27][28] Some investigators study therapeutic strategies based on methylation inhibitors, 14,29 others are working to develop DNA methylation alterations as useful diagnostic biomarkers. 30 To date, most efforts in this area have focused broadly on describing the epigenetic landscape of prostate cancer.…”

Section: Methylation In Prostate Cancermentioning

confidence: 99%

A three‐gene DNA methylation biomarker accurately classifies early stage prostate cancer

et al. 2019

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Background We identify and validate accurate diagnostic biomarkers for prostate cancer through a systematic evaluation of DNA methylation alterations. Materials and methods We assembled three early prostate cancer cohorts (total patients = 699) from which we collected and processed over 1300 prostatectomy tissue samples for DNA extraction. Using real‐time methylation‐specific PCR, we measured normalized methylation levels at 15 frequently methylated loci. After partitioning sample sets into independent training and validation cohorts, classifiers were developed using logistic regression, analyzed, and validated. Results In the training dataset, DNA methylation levels at 7 of 15 genomic loci (glutathione S‐transferase Pi 1 [GSTP1], CCDC181, hyaluronan, and proteoglycan link protein 3 [HAPLN3], GSTM2, growth arrest‐specific 6 [GAS6], RASSF1, and APC) showed large differences between cancer and benign samples. The best binary classifier was the GAS6/GSTP1/HAPLN3 logistic regression model, with an area under these curves of 0.97, which showed a sensitivity of 94%, and a specificity of 93% after external validation. Conclusion We created and validated a multigene model for the classification of benign and malignant prostate tissue. With false positive and negative rates below 7%, this three‐gene biomarker represents a promising basis for more accurate prostate cancer diagnosis.

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“…The enhancer of zeste homolog 2 (EZH2) is a core component of the polycomb repressive complex 2 (PRC2) that induces silencing of the target genes via methylation of histone H3 lysine 27. Elevated expression of EZH2 results in cancer progression through histone methylation‐driven tumor cells dedifferentiation . Previous results reveal that BRCA1 is a negative regulator of PRC2‐dependent H3K27 methylation at the PRC2 target genetic loci and that decrease of BRCA1 inhibits differentiation of embryonic stem cells, induces breast CSC population and enhances aggressiveness of breast tumors .…”

Section: Introductionmentioning

confidence: 99%

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Gorodetska

Lukiyanchuk

Peitzsch

et al. 2019

Intl Journal of Cancer

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Prostate cancer (PCa) is the second most common malignancy and the sixth leading cause of cancer-related death among men worldwide. Prostate carcinogenesis is driven by the accumulation of genetic and epigenetic aberrations, which regulate cancer cell transition between a stem-and nonstem-cell state and accelerate tumor evolution. Elevated expression of enhancer of zeste homolog 2 (EZH2) histone methyltransferase, a core member of the polycomb repressive complex 2 (PRC2), results in cancer progression through histone methylation-driven tumor cells dedifferentiation. Previous studies demonstrated that tumor suppressor breast cancer 1 (BRCA1) is a negative regulator of PRC2-dependent H3K27 methylation. Our recent studies revealed that inhibition of EZH2-mediated histone methylation radiosensitizes prostate cancer stem cells (CSCs) population. However, the link between BRCA1 and EZH2 in regulation of prostate CSCs remains elusive. Present study demonstrated that BRCA1 and EZH2 are coregulated in patients' tumors and PCa cell lines, and cooperate in regulation of CSC phenotype and properties. Knockdown of BRCA1 expression significantly increases the number and the size of tumor spheres. Inhibition of BRCA1 and EZH2 expression leads to an increase of aldehyde dehydrogenase (ALDH)-positive cell population that is, at least partially, attributed to the upregulation of ALDH1A3 protein. Treatment with a global histone methylation inhibitor 3-Deazaneplanocin A abrogates this regulation, downregulates BRCA1 and EZH2 expression and has an inhibitory effect on the tumorigenic properties of radioresistant PCa cells in vivo. We found that EZH2/BRCA1 signaling mechanisms play an important role in the maintenance of prostate CSC properties and may be a promising target for tumor treatment.

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Epigenetic Regulation in Prostate Cancer Progression

Cited by 56 publications

References 150 publications

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

A three‐gene DNA methylation biomarker accurately classifies early stage prostate cancer

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

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