The importance of DNA methylation in prostate cancer development

Massie, Charles E.; Mills, Ian G.; Lynch, Andy G.

doi:10.1016/j.jsbmb.2016.04.009

Cited by 128 publications

(133 citation statements)

References 130 publications

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“…The changes in CpG methylation in PCa progression have been comprehensively reviewed by Lynch and co-workers [132]. They highlighted the consistency of methylation at the promoter of certain genes, for example Glutathione S -Transferase Pi 1 (GSTP1).…”

Section: Prostate Cancer As a Model Of The Interplay Between Genommentioning

confidence: 99%

“…Thus, for each of the 21 DNA methylation pathway genes the negative and positive correlations (Pearson correlation either <−0.6 or >0.6) of expression was determined. Only five DNA methylation pathway genes had strong correlations and subsequently, the enrichment of the 165 common targets of DNA methylation from the Lynch et al review [132] was measured within these correlated genes, using a hypergeometric test.…”

Section: Bioinformatic Approaches To Reveal Associations Between Dmentioning

confidence: 99%

“…Gene expression was measured as normal tissue relative Z -scores of all genes detectable in at least 80% of tumors. Cluster membership significantly identifies aggressive tumors ( p < 0.006); ( B ) The negative and positive correlation (Pearson correlation either <−0.6 or >0.6) for each of these commonly altered genes from the DNA methylation pathway ( n = 21) and all other detectable genes in the TCGA cohort ( n = 16,785) was measured and the enrichment of the 165 common targets of DNA methylation from the Lynch et al review [132] was measured using a hypergeometric test. Only the indicated genes had significant correlation with all genes and significant enrichment of the targets of DNA methylation; ( C ) Heatmap illustrating common and significantly altered mRNA expression of genes that significantly correlate with Indolethylamine N -Methyltransferase (INMT) and Methionine Adenosyltransferase 2B (MAT2B) and are known targets of DNA methylation in TCGA PRAD cohort.…”

Section: Figurementioning

confidence: 99%

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The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer

2017

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The process of DNA CpG methylation has been extensively investigated for over 50 years and revealed associations between changing methylation status of CpG islands and gene expression. As a result, DNA CpG methylation is implicated in the control of gene expression in developmental and homeostasis processes, as well as being a cancer-driver mechanism. The development of genome-wide technologies and sophisticated statistical analytical approaches has ushered in an era of widespread analyses, for example in the cancer arena, of the relationships between altered DNA CpG methylation, gene expression, and tumor status. The remarkable increase in the volume of such genomic data, for example, through investigators from the Cancer Genome Atlas (TCGA), has allowed dissection of the relationships between DNA CpG methylation density and distribution, gene expression, and tumor outcome. In this manner, it is now possible to test that the genome-wide correlations are measurable between changes in DNA CpG methylation and gene expression. Perhaps surprisingly is that these associations can only be detected for hundreds, but not thousands, of genes, and the direction of the correlations are both positive and negative. This, perhaps, suggests that CpG methylation events in cancer systems can act as disease drivers but the effects are possibly more restricted than suspected. Additionally, the positive and negative correlations suggest direct and indirect events and an incomplete understanding. Within the prostate cancer TCGA cohort, we examined the relationships between expression of genes that control DNA methylation, known targets of DNA methylation and tumor status. This revealed that genes that control the synthesis of S-adenosyl-l-methionine (SAM) associate with altered expression of DNA methylation targets in a subset of aggressive tumors.

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Section: Prostate Cancer As a Model Of The Interplay Between Genommentioning

confidence: 99%

Section: Bioinformatic Approaches To Reveal Associations Between Dmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer

2017

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“…To date, methylation of the AR promoter region was primarily investigated in relation to prostate cancer, where DNA hypermethylation of the AR promoter region occurs leading to AR downregulation (74, 75). As low levels of testosterone are associated with depression in men and hypermethylation of the AR promoter region reduces testosterone signaling and action at target cells, hypermethylation of the AR might be associated to neuropsychiatric manifestations in men, including depression, AUDs, and suicidal behavior.…”

Section: Epigenetic Risk Constellationmentioning

confidence: 99%

Neuroendocrinology of a Male-Specific Pattern for Depression Linked to Alcohol Use Disorder and Suicidal Behavior

et al. 2017

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Epidemiological studies show low rates of diagnosed depression in men compared to women. At the same time, high rates of alcohol use disorders (AUDs) and completed suicide are found among men. These data suggest that a male-specific pattern for depression may exist that is linked to AUDs and suicidal behavior. To date, no underlying neuroendocrine model for this specific pattern of male depression has been suggested. In this paper, we integrate findings related to this specific pattern of depression with underlying steroid secretion patterns, polymorphisms, and methylation profiles of key genes in order to detail an original neuroendocrine model of male-specific depression. Low circulating levels of sex steroids seem to increase the vulnerability for male depression, while concomitant high levels of glucocorticoids further intensify this vulnerability. Interactions of hypothalamus–pituitary–gonadal (HPG) and hypothalamus–pituitary–adrenocortical (HPA) axis-related hormones seem to be highly relevant for a male-specific pattern of depression linked to AUDs and suicidal behavior. Moreover, genetic variants and the epigenetic profiles of the androgen receptor gene, well-known depression related genes, and HPA axis-related genes were shown to further interact with men’s steroid secretion and thus may further contribute to the proposed male-specific pattern for depression. This mini-review points out the multilevel interactions between the HPG and HPA axis for a male-specific pattern of depression linked to AUDs and suicidal behavior. An integration of multilevel interactions within the three-hit concept of vulnerability and resilience concludes the review.

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“…Alternative TSS regulation by DNA methylation at RASSF1 and APC has been reported in prostate cancer tissue and shown by treatment of cells with 5-aza-2′-deoxycytidine (Massie et al 2016). Another intriguing example is prostate cancer-specific demethylation of an internal promoter in MCT2 (Pertega-Gomes et al 2015).…”

Section: Alternative Transcription Start Sitesmentioning

confidence: 96%

WOMEN IN CANCER THEMATIC REVIEW: Diverse functions of DNA methylation: implications for prostate cancer and beyond

Sweet¹,

Ting²

2016

Endocrine-Related Cancer

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Prostate cancer is one of the most common malignancies in men worldwide. Current clinical screening ensures that most prostate cancers are diagnosed while still organ confined, but disease outcome is highly variable. Thus, a better understanding of the molecular features contributing to prostate cancer aggressiveness is being sought. For many cancers, aberrant genome-wide patterns of cytosine DNA methylation in CpG dinucleotides distinguish tumor from normal tissue and contribute to disease progression by altering the transcriptome. In prostate cancer, recent genomic studies identified cancer and high grade-specific differential DNA methylation in gene promoters, gene bodies, gene 3′ ends and at distal regulatory elements. Using examples from developmental and disease systems, we will discuss how DNA methylation in each of these genomic contexts can contribute to transcriptome diversity by modulating transcription initiation, alternative transcription start site selection, alternative pre-mRNA splicing and alternative polyadenylation. Alternative transcripts from the same gene often exhibit altered protein-coding potential, translatability, stability and/or localization. All of these can have functional consequences in cells. In future work, it will be important to determine if DNA methylation abnormalities in prostate cancer modify the transcriptome through some or all of these mechanisms and if these DNA methylation-mediated transcriptome alterations impact prostate tumorigenesis and aggressiveness.

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The importance of DNA methylation in prostate cancer development

Cited by 128 publications

References 130 publications

The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer

The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer

Neuroendocrinology of a Male-Specific Pattern for Depression Linked to Alcohol Use Disorder and Suicidal Behavior

WOMEN IN CANCER THEMATIC REVIEW: Diverse functions of DNA methylation: implications for prostate cancer and beyond

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