Alterations of 5-Hydroxymethylcytosine in Human Cancers

Mariani, Christopher J.; Madžo, Jozef; Moen, Erika L.; Yesilkanal, Ali E.; Godley, Lucy A.

doi:10.3390/cancers5030786

Cited by 46 publications

(29 citation statements)

References 143 publications

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“…Moreover, recent advances suggest that distinct aberrant genetic and epigenetic events, including abnormal histone modification and DNA methylation, are all important cancer hallmarks. The discovery of the ten-eleven translocase (TET) enzyme family, which converts 5-mC to 5-hmC, has added an additional layer of complexity to the epigenetic regulation of DNA methylation (2–7). Multiple studies are currently focusing on investigating the effect of epigenetic changes during tumor development and progression (2–7).…”

Section: Introductionmentioning

confidence: 99%

“…The discovery of the ten-eleven translocase (TET) enzyme family, which converts 5-mC to 5-hmC, has added an additional layer of complexity to the epigenetic regulation of DNA methylation (2–7). Multiple studies are currently focusing on investigating the effect of epigenetic changes during tumor development and progression (2–7). Research on DNA methylation has been of particular interest recently, mostly targeting specific genetic loci and their promoters (8).…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer

Tucker

Getchell

McCarthy

et al. 2018

Clinical Cancer Research

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Purpose A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. Experimental Design We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. Results This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy in vitro and in vivo, decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease. Conclusions Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer

Tucker

Getchell

McCarthy

et al. 2018

Clinical Cancer Research

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“…5hmC profiling in breast and liver cancer samples by RRHP Previous studies on the role of 5hmC in cancer have shown loss of 5hmC is commonly associated with tumor development in both hematological diseases and solid tumors [15]. However, it is not clear whether the decrease of 5hmC is a result of global 5mC reduction, which is also a hallmark of tumorgenesis, or due to a different epigenetic regulation.…”

Section: Cross-platform Validations and Correlationmentioning

confidence: 88%

RRHP: a tag-based approach for 5-hydroxymethylcytosine mapping at single-site resolution

Petterson¹,

Chung²,

Tan³

et al. 2014

Genome Biol

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Current methods for genomic mapping of 5-hydroxymethylcytosine (5hmC) have been limited by either costly sequencing depth, high DNA input, or lack of single-base resolution. We present an approach called Reduced Representation 5-Hydroxymethylcytosine Profiling (RRHP) to map 5hmC sites at single-base resolution by exploiting the use of beta-glucosyltransferase to inhibit enzymatic digestion at the junction where adapters are ligated to a genomic library. Therefore, only library fragments presenting glucosylated 5hmC residues at the junction are sequenced. RRHP can detect sites with low 5hmC abundance, and when combined with RRBS data, 5-methylcytosine and 5-hydroxymethylcytosine can be compared at a specific site.

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“…However, emerging evidence links many diseases to both the sequence and the methylation state of the DNA (absence or presence of a methyl group to the DNA backbone)(Berger et al 2009; Bird 2002; Esteller 2007; Pastor et al 2011; Portela and Esteller 2010; Rando and Verstrepen 2007; Surani et al 2007; Thu et al 2010). Most notably, although the fundamental genetic code is not altered by the presence of the methyl group, the function can be significantly altered, disrupting normal cell behavior (Branco et al 2012; Chen and Riggs 2005; Esteller 2007; Li and O’Neill 2013; Mariani et al 2013; Riggs 2002). The regulation of cellular function can be traced to guanine-cytosine rich sequences known as CpG islands interspersed throughout the genome but more prominent in the promoter regions (Berger et al 2009; Bird 2002).…”

Section: Introductionmentioning

confidence: 99%

Label free detection of 5′hydroxymethylcytosine within CpG islands using optical sensors

Hawk

Armani

2015

Biosensors and Bioelectronics

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Significant research has been invested in correlating genetic variations with different disease probabilities. Recently, it has become apparent that other DNA modifications, such as the addition of a methyl or hydroxymethyl group to cytosine, can also play a role. While these modifications do not change the sequence, they can negatively impact the function. Therefore, it is critical to be able to both read the genetic code and identify these modifications. Currently, the detection of hydroxymethylated cytosine (5′hmC) and the two closely related variants, cytosine (C) and 5′methylcytosine (5′mC), relies on a combination of nucleotide modification steps, followed by PCR and gene sequencing. However, this approach is not ideal because transcription errors which are inherent to the PCR process can be misinterpreted as fluctuations in the relative C:5′mC:5′hmC concentrations. As such, an alternative method which does not rely on PCR or nucleotide modification is desirable. One approach is based on label-free optical resonant cavity sensors. In the present work, toroidal resonant cavity sensors are functionalized with antibodies to enable label-free detection and discrimination between C, 5′mC, and 5′hmC in real-time without PCR. Specifically, epoxide chemistry is used to covalently attach the 5′hmC antibody to the surface of the cavity. Subsequently, to thoroughly characterize the sensor platform, detection of C, 5′mC, and 5′hmC is performed over a concentration range from pM to nM. At low (pM) concentrations, the hydroxymethylated cytosine produces a significantly larger signal than the structurally similar epigenetic markers; thus demonstrating the applicability of this platform.

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Alterations of 5-Hydroxymethylcytosine in Human Cancers

Cited by 46 publications

References 143 publications

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer

RRHP: a tag-based approach for 5-hydroxymethylcytosine mapping at single-site resolution

Label free detection of 5′hydroxymethylcytosine within CpG islands using optical sensors

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