Clinical Advances in Hypomethylating Agents Targeting Epigenetic Pathways

Cang, Shundong; Lu, Qianjin; Ma, Y.; Liu, D.

doi:10.2174/156800910791517217

Cited by 19 publications

(6 citation statements)

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“…MiRNAs can be manipulated by antisense oligonucleotides that inactivate mRNA before translation to miRNAs and by epigenetic modifications of methylation‐sensitive genes that express the miRNAs . All elements have been manipulated in experimental models of immune‐mediated and malignant diseases .…”

Section: Resultsmentioning

confidence: 99%

Epigenetic changes and their implications in autoimmune hepatitis

Czaja

2018

Eur J Clin Investigation

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Background: The genetic risk of autoimmune hepatitis is insufficient to explain the observed risk, and epigenetic changes may explain disparities in disease occurrence in different populations within and between countries. The goal of this review was to examine how epigenetic changes induced by the environment or inherited as a phenotypic trait may affect autoimmune hepatitis and be amenable to therapeutic intervention. Materials and methods: Pertinent abstracts were identified in PubMed by multiple search terms. The number of abstracts reviewed was 1689, and the number of full-length articles reviewed exceeded 150. Results: Activation of pro-inflammatory genes in autoimmune disease is associated with hypomethylation of deoxyribonucleic acid and modification of histones within chromatin. Organ-specific microribonucleic acids can silence genes by marking messenger ribonucleic acids for degradation, and they can promote inflammatory activity or immunosuppression. High circulating levels of the microribonucleic acids 21 and 122 have been demonstrated in autoimmune hepatitis, and they may increase production of pro-inflammatory cytokines. Microribonucleic acids are also essential for maintaining regulatory T cells. Drugs, pollutants, infections, diet and ageing can induce inheritable epigenetic changes favouring autoimmunity. Reversal is feasible by manipulating enzymes, transcription factors, gene-silencing molecules and toxic exposures or by administering methyl donors and correcting vitamin D deficiency. Gene targets, site specificity, efficacy and consequences are uncertain. Conclusions: Potentially reversible epigenetic changes may affect the occurrence and outcome of autoimmune hepatitis, and investigations are warranted to determine the nature of these changes, key genomic targets, and feasible interventions and their consequences.

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Section: Resultsmentioning

confidence: 99%

Epigenetic changes and their implications in autoimmune hepatitis

Czaja

2018

Eur J Clin Investigation

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“…Every cell process is permeated by epigenetic regulation, from cancer 175 to autoimmune diseases 176 . The understanding of these mechanisms and the identification of target molecules are expected to lead to new classes of therapeutical molecules, coined “epigenetic therapies” 177,178 . We foresee that only a common effort between researchers involved in human and experimental autoimmunity and the use of powerful tools such as MZ twins will soon provide fascinating developments in the relatively young field of epigenomics.…”

Section: Where We Are and What Is Next For The Epigenetics Of Autoimmmentioning

confidence: 99%

The epigenetics of autoimmunity

et al. 2011

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The etiology of autoimmune diseases remains largely unknown. Concordance rates in monozygotic twins are lower than 50% while genome-wide association studies propose numerous significant associations representing only a minority of patients. These lines of evidence strongly support other complementary mechanisms involved in the regulation of genes expression ultimately causing overt autoimmunity. Alterations in the post-translational modification of histones and DNA methylation are the two major epigenetic mechanisms that may potentially cause a breakdown of immune tolerance and the perpetuation of autoimmune diseases. In recent years several studies both in clinical settings and experimental models proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and other autoimmune diseases, in some cases based on mechanistical observations. We herein discuss what we currently know and what we expect will come in the next future. Ultimately, epigenetic treatments already being used in oncology may soon prove beneficial also in autoimmune diseases.

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“…DNA methyltransferase inhibitors, ie, azacitidine (5-azacytidine, 5AC), 5-aza-2′-deoxycytidine (decitabine) and pyrimidin-2-one β-ribofuranoside (zebularine) have been studied in the preclinical setting, and even in clinical trials. 77 , 78 Under equivalent and clinically relevant treatment schemes, the three DNA methyltransferase inhibitors left a distinct gene expression profile in cells, indicating that these drugs are not identical in function. Differences in structure and cellular pharmacology between the three DNA methyltransferase inhibitors may account for the diversity observed.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of DAPK promoter hypermethylation in lung cancer: a meta-analysis

Li¹,

Zhu²,

Cheng³

et al. 2015

DDDT

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Death-associated protein kinase 1 (DAPK) is an important serine/threonine kinase involved in various cellular processes, including apoptosis, autophagy, and inflammation. DAPK expression and activity are deregulated in a variety of diseases including cancer. Methylation of the DAPK gene is common in many types of cancer and can lead to loss of DAPK expression. However, the association between DAPK promoter hypermethylation and the clinicopathological significance of lung cancer remains unclear. In this study, we searched the MEDLINE, PubMed, Web of Science, and Scopus databases, systematically investigated the studies of DAPK promoter hypermethylation in lung cancer and quantified the association between DAPK promoter hypermethylation and its clinicopathological significance by meta-analysis. We observed that the frequency of DAPK methylation was significantly higher in lung cancer than in non-malignant lung tissues (odds ratio 6.02, 95% confidence interval 3.17–11.42, P<0.00001). The pooled results also showed the presence of a prognostic impact of DAPK gene methylation in lung cancer patients (odds ratio 3.63, 95% confidence interval 1.09–12.06, P=0.04). In addition, we summarized these findings and discuss tumor suppressor function, clinicopathological significance, and potential drug targeting of DAPK in lung cancer.

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Clinical Advances in Hypomethylating Agents Targeting Epigenetic Pathways

Cited by 19 publications

References 0 publications

Epigenetic changes and their implications in autoimmune hepatitis

Epigenetic changes and their implications in autoimmune hepatitis

The epigenetics of autoimmunity

Clinical significance of DAPK promoter hypermethylation in lung cancer: a meta-analysis

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