Epigenetic inactivation of tumour suppressor coding and non-coding genes in human cancer: an update

Llinàs‐Arias, Pere; Esteller, Manel

doi:10.1098/rsob.170152

Cited by 73 publications

(50 citation statements)

References 183 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cytosine methylation (5′‐methylcytosine, 5meC), also called DNA methylation, is the leading epigenetic mechanism of DNA in eukaryotes that is involved in gene regulation processes in cells (Schubeler, ). The addition of methyl groups to cytosines can alter gene expression levels with respect to the modification locations along the gene sections, that is, within or between CpG islands (cytosine guanine repeats), within coding or noncoding regions, and/or within promoters (Llinas‐Arias & Esteller, ; Zabet, Catoni, Prischi, & Paszkowski, ). The changes in cytosine methylation have currently been found to be associated with many diseases, such as cancer (Bhattacharyya et al, ; Morita et al, ; Wei et al, ) and neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

Enhanced immunological detection of epigenetic modifications of DNA in healthy and cancerous cells by fluorescence microscopy

Çelik-Uzuner

2019

Microsc Res Tech

View full text Add to dashboard Cite

Epigenetic modifications of DNA, including methylation, hydroxymethylation, formylation, and carboxylation of cytosines, are proposed to function in gene regulation during reproduction and development. Changes in cytosine methylation are associated with a range of diseases, such as cancer. Immunofluorescence uses specific antibodies to quantitatively detect the global amount of cytosine modifications by fluorescence microscopy. The most critical stage of immunofluorescence is the antigen retrieval to remove the protein content around the DNA, allowing specific antibodies to bind to DNA epitopes. Acid treatments have commonly been used for antigen retrieval. Previously, trypsin was added after acid in the protocol, which increased the amount of detectable DNA methylation. In this study, the protocol was further enhanced by the addition of pepsin, which is able to target charged hydrophobic amino acids in proteins, unlike trypsin, which breaks positive hydrophilic amino acids. The global levels of cytosine modifications in CF‐1, HeLa, and AR42J cells were compared using this protocol. In all cells, the sequential treatment of trypsin and pepsin increased the specificity of the staining. With the synergistic effect of the two enzymes, it is possible to target different protein groups packaging DNA molecules and removing them effectively. The findings suggest that this revised protocol can be conveniently used for each cytosine modification in the cells examined, and should be optimized for other cells. These new antigen retrieval conditions may more accurately detect the changes in cytosine modifications during development and in diseases.

show abstract

Section: Introductionmentioning

confidence: 99%

Enhanced immunological detection of epigenetic modifications of DNA in healthy and cancerous cells by fluorescence microscopy

Çelik-Uzuner

2019

Microsc Res Tech

View full text Add to dashboard Cite

show abstract

“…Cellular response to radiation and intrinsic radiosensitivity are highly influenced by the function of tumour suppressor genes, often epigenetically silenced in tumours [23]. In this study, we therefore aimed to identify loci of DNA methylation alterations in paediatric GSCs following radiation in order to reveal alterations in sites or regions which could mediate the effects of radiation.…”

Section: Discussionmentioning

confidence: 99%

Accumulation of DNA methylation alterations in paediatric glioma stem cells following fractionated dose irradiation

et al. 2020

View full text Add to dashboard Cite

Background: Radiation is an important therapeutic tool. However, radiotherapy has the potential to promote coevolution of genetic and epigenetic changes that can drive tumour heterogeneity, formation of radioresistant cells and tumour relapse. There is a clinical need for a better understanding of DNA methylation alterations that may follow radiotherapy to be able to prevent the development of radiation-resistant cells. Methods:We examined radiation-induced changes in DNA methylation profiles of paediatric glioma stem cells (GSCs) in vitro. Five GSC cultures were irradiated in vitro with repeated doses of 2 or 4 Gy. Radiation was given in 3 or 15 fractions. DNA methylation profiling using Illumina DNA methylation arrays was performed at 14 days postradiation. The cellular characteristics were studied in parallel. Results: Few fractions of radiation did not result in significant accumulation of DNA methylation alterations. However, extended dose fractionations changed DNA methylation profiles and induced thousands of differentially methylated positions, specifically in enhancer regions, sites involved in alternative splicing and in repetitive regions. Radiation induced dose-dependent morphological and proliferative alterations of the cells as a consequence of the radiation exposure.Conclusions: DNA methylation alterations of sites with regulatory functions in proliferation and differentiation were identified, which may reflect cellular response to radiation stress through epigenetic reprogramming and differentiation cues.

show abstract

“…This leads not only to the restraint of TE expression and transposition (Jacobs et al, 2014), but also to the domestication of their regulatory sequences (e.g., promoters, enhancers) for the advantage of a cell (Ecco et al, 2016;Imbeault et al, 2017;Trono, 2015). It is noteworthy that the genes under the control of KRAB-ZNF may undergo not only repression, but also activation (Busiello et al, 2017;Frietze et al, 2010;Lupo et al, 2013). At this stage, it is difficult to envisage how the cancer-associated KRAB-ZNFs affect tumor behavior, and further functional analyses are necessary to answer this question.…”

Section: Discussionmentioning

confidence: 99%

“…Alterations to the DNA methylation profile frequently correlate with changes affecting chromatin state. CpG island hypermethylation in cancer cells is associated with a decrease in histone active marks: histone H3 and H4 acetylation, H3K4 trimethylation, and gain of repressive marks: H3K9me3 and H3K27me3 (Llinas‐Arias and Esteller, ). Moreover, the expression of many chromatin modifiers is often deregulated in the tumor (Dawson and Kouzarides, ).…”

Section: Introductionmentioning

confidence: 99%

“…Kr€ uppel-associated box domain zinc finger proteins (KRAB-ZNFs) are the most abundant family of epigenetic repressors found only in tetrapod vertebrates (Lupo et al, 2013;Ma et al, 2014). The human genome harbors over 800 KRAB-ZNF transcripts encoding functional proteins, splicing variants, and pseudogenes (Corsinotti et al, 2013;Huntley et al, 2006) that may be involved in development, metabolism, proliferation, and carcinogenesis (Ecco et al, 2017;Lupo et al, 2013). Upon binding to DNA, KRAB-ZNFs trigger transcriptional repression through interaction with KAP1 (KRAB-associated protein-1), also known as TRIM28 (Tripartite-motif containing 28).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The expression signature of cancer‐associated KRAB‐ZNF factors identified in TCGA pan‐cancer transcriptomic data

et al. 2019

View full text Add to dashboard Cite

The KRAB ‐ ZNF (Krüppel‐associated box domain zinc finger) gene family is composed of a large number of highly homologous genes, gene isoforms, and pseudogenes. The proteins encoded by these genes, whose expression is often tissue‐specific, act as epigenetic suppressors contributing to the addition of repressive chromatin marks and DNA methylation. Due to its high complexity, the KRAB ‐ ZNF family has not been studied in sufficient detail, and the involvement of its members in carcinogenesis remains mostly unexplored. In this study, we aimed to provide a comprehensive description of cancer‐associated KRAB ‐ ZNF s using publicly available The Cancer Genome Atlas pan‐cancer datasets. We analyzed 6727 tumor and normal tissue samples from 16 cancer types. Here, we showed that a small but distinctive cluster of 16 KRAB ‐ ZNF s is commonly upregulated across multiple cancer cohorts in comparison to normal samples. We confirmed these observations in the independent panels of lung and breast cancer cell lines and tissues. This upregulation was also observed for most of the KRAB ‐ ZNF splicing variants, whose expression is simultaneously upregulated in tumors compared to normal tissues. Finally, by analyzing the clinicopathological data for breast and lung cancers, we demonstrated that the expression of cancer‐associated KRAB ‐ ZNF s correlates with patient survival, tumor histology, and molecular subtyping. Altogether, our study allowed the identification and characterization of KRAB ‐ ZNF factors that may have an essential function in cancer biology and thus potential to become novel oncologic biomarkers and treatment targets.

show abstract

Epigenetic inactivation of tumour suppressor coding and non-coding genes in human cancer: an update

Cited by 73 publications

References 183 publications

Enhanced immunological detection of epigenetic modifications of DNA in healthy and cancerous cells by fluorescence microscopy

Enhanced immunological detection of epigenetic modifications of DNA in healthy and cancerous cells by fluorescence microscopy

Accumulation of DNA methylation alterations in paediatric glioma stem cells following fractionated dose irradiation

The expression signature of cancer‐associated KRAB‐ZNF factors identified in TCGA pan‐cancer transcriptomic data

Contact Info

Product

Resources

About