Post-treatment circulating plasma BMP6 mRNA and H3K27 methylation levels discriminate metastatic prostate cancer from localized disease

Deligezer, Ugur; Yaman, Fulya; Darendeliler, Emin; Dizdar, Yavuz; Holdenrieder, Stefan; Kovancilar, Müge; Dalay, Nejat

doi:10.1016/j.cca.2010.05.040

Cited by 48 publications

(37 citation statements)

References 33 publications

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“…While it remains to be established whether the release of H3K27me3 into the circulation might directly reflect greater exchanges between activating/repressive epigenetics marks in target (e.g., hepatic and/or tumor) tissues, it was noteworthy that the significant augmentation of circulating H3K27me3 promoted by adding metformin to standard neoadjuvant treatment occurred solely in those cancer patients who achieved a complete tumor response in both the breast and axillary lymph nodes. Given that the release of post‐translational modifications of histone proteins from cells into the blood circulation has been suggested to mirror cell‐specific and disease‐related processes (Deligezer et al, 2010; Gezer et al., 2015; McAnena, Brown & Kerin, 2017), our findings might reveal a novel, noninvasive method to dynamically monitor the capacity of metformin to correct or reset the abnormal chromatin state of cancer and/or aging cells.…”

Section: Discussionmentioning

confidence: 99%

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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SummaryMetformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure‐ and ligand‐based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3‐specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low‐density lipoprotein receptor‐deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft‐bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

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Section: Discussionmentioning

confidence: 99%

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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“…In each run, 20 µL of plasma was analyzed by solid-phase sandwich enzyme-linked immunosorbent assay (ELISA), using monoclonal antibodies to detect H3K4me3 acetylated H3K9ac (EpiQuik Assay Kit, Epigentek, Brooklyn, NY, USA) (Deligezer et al, 2010). We used a Synergy HT-BioTek spectrophotometer to read 490 nm absorbance (OD), which was assumed proportional to the concentration of modified histones (Deligezer et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

Extracellular histones mediate the effects of metal-rich air particles on blood coagulation

Cantone

Angelici

Bollati

et al. 2014

Environmental Research

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Background Epidemiological studies have shown associations of particulate matter (PM) exposure with hypercoagulability and thrombosis. Extracellular circulating histones have recently been identified as novel mediators of inflammatory and procoagulant responses. The potential roles of extracellular histones in PM-related hypercoagulability have yet not been investigated. Objectives In 63 steel workers, we evaluated the effects of exposure to PM and PM metal components on two extracellular histone modifications (H3K4me3 and H3K9ac); and the association of H3K4me3 and H3K9ac with coagulation markers. Methods Extracellular H3K4me3 and H3K9ac were determined in plasma through enzyme-linked immunosorbent assays. Coagulation markers included endogenous thrombin potentials (ETPs), tissue-type plasminogen activator antigen (t-PA) and d-dimer. Exposure to PM with aerodynamic diameters <1 µm (PM1) or <10 µm (PM10) and PM10 metal components were estimated for each participant. Results The coagulation marker ETP, measured in the presence of soluble thrombomodulin (ETP TM+), showed significant positive associations with PM1 (β=107.84, p=0.03), PM10 (β=83.06, p=0.02), and zinc (β=75.14, p=0.03); and a marginal association with iron (β=122.58, p=0.07). Additional PM effects were observed on t-PA, D-dimer, and ETP TM+. PM1 exposure was associated with increased plasma H3K4me3 and H3K9ac (β=0.20, p=0.02; β=0.16, p=0.05, respectively). H3K4me3, but not H3K9ac, was associated with zinc (β=0.13, p=0.03) and iron (β=0.32, p=0.01) contained in PM. ETP TM+ was increased in association with higher plasma H3K4me3 (β=0.50, p=0.05) and H3K9ac (β=0.54, p=0.05). Conclusions This observational study suggests potential roles of extracellular histones in PM-induced hypercoagulability. Experimental studies are warranted to further characterize these findings.

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“…H3K27me3 displayed an inverse distribution compared to BMP6 mRNA and was significantly lower in patients with metastatic disease than in those with localized or local advanced disease. This study provides evidence that post-treatment analysis of cBMP6 mRNA and H3K27me3 in plasma may be used to distinguish metastatic prostate cancer from organ confined, local disease (Deligezer et al, 2010).…”

Section: Epigenetic Analyses Of Cell-free Dnamentioning

confidence: 80%

Clinical Relevance of Circulating Nucleic Acids in Blood of Prostate Cancer Patients

Schwarzenbach¹

2011

Prostate Cancer - From Bench to Bedside

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Post-treatment circulating plasma BMP6 mRNA and H3K27 methylation levels discriminate metastatic prostate cancer from localized disease

Cited by 48 publications

References 33 publications

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Extracellular histones mediate the effects of metal-rich air particles on blood coagulation

Clinical Relevance of Circulating Nucleic Acids in Blood of Prostate Cancer Patients

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