scholarly journals Epigenetic therapy of novel tumour suppressor ZAR1 and its cancer biomarker function

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Verena Deutschmeyer ◽  
Janina Breuer ◽  
Sara K. Walesch ◽  
Anna M. Sokol ◽  
Johannes Graumann ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Zinc Finger ◽  
Cpg Island ◽  
Clinical Importance ◽  
Global Gene Expression ◽  
Cancer Biomarker ◽  
Tumour Suppressor ◽  
Epigenetic Therapy ◽  
Lung Carcinogenesis ◽  
Dna Hypermethylation

Abstract Background Cancer still is one of the leading causes of death and its death toll is predicted to rise further. We identified earlier the potential tumour suppressor zygote arrest 1 (ZAR1) to play a role in lung carcinogenesis through its epigenetic inactivation. Results We are the first to report that ZAR1 is epigenetically inactivated not only in lung cancer but also across cancer types, and ZAR1 methylation occurs across its complete CpG island. ZAR1 hypermethylation significantly correlates with its expression reduction in cancers. We are also the first to report that ZAR1 methylation and expression reduction are of clinical importance as a prognostic marker for lung cancer and kidney cancer. We further established that the carboxy (C)-terminally present zinc-finger of ZAR1 is relevant for its tumour suppression function and its protein partner binding associated with the mRNA/ribosomal network. Global gene expression profiling supported ZAR1's role in cell cycle arrest and p53 signalling pathway, and we could show that ZAR1 growth suppression was in part p53 dependent. Using the CRISPR-dCas9 tools, we were able to prove that epigenetic editing and reactivation of ZAR1 is possible in cancer cell lines. Conclusion ZAR1 is a novel cancer biomarker for lung and kidney, which is epigenetically silenced in various cancers by DNA hypermethylation. ZAR1 exerts its tumour suppressive function in part through p53 and through its zinc-finger domain. Epigenetic therapy can reactivate the ZAR1 tumour suppressor in cancer.

scholarly journals Site-Specific DNA Demethylation as a Potential Target for Cancer Epigenetic Therapy

2020 ◽  
Vol 13 ◽  
pp. 251686572096480
Author(s):  
Sultan Abda Neja
Keyword(s):  
Cpg Island ◽  
Causal Effect ◽  
Dna Methyltransferases ◽  
Dna Demethylation ◽  
Epigenetic Therapy ◽  
In Vivo Model ◽  
Transcription Activator ◽  
Dna Hypermethylation ◽  
Site Specific

Aberrant promoter DNA hypermethylation is a typical characteristic of cancer and it is often seen in malignancies. Recent studies showed that regulatory cis-elements found up-stream of many tumor suppressor gene promoter CpG island (CGI) attract DNA methyltransferases (DNMT) that hypermethylates and silence the genes. As epigenetic alterations are potentially reversible, they make attractive targets for therapeutic intervention. The currently used decitabine (DAC) and azacitidine (AZA) are DNMT inhibitors that follow the passive demethylation pathway. However, they lead to genome-wide demethylation of CpGs in cells, which makes difficult to use it for causal effect analysis and treatment of specific epimutations. Demethylation through specific demethylase enzymes is thus critical for epigenetic resetting of silenced genes and modified chromatins. Yet DNA-binding factors likely play a major role to guide the candidate demethylase enzymes upon its fusion. Before the advent of clustered regulatory interspaced short palindromic repeats (CRISPR), both zinc finger proteins (ZNFs) and transcription activator-like effector protein (TALEs) were used as binding platforms for ten-eleven translocation (TET) enzymes and both systems were able to induce transcription at targeted loci in an in vitro as well as in vivo model. Consequently, the development of site-specific and active demethylation molecular trackers becomes more than hypothetical to makes a big difference in the treatment of cancer in the future. This review is thus to recap the novel albeit distinct studies on the potential use of site-specific demethylation for the development of epigenetic based cancer therapy.

Aberrant Epigenetic Regulation: A Central Contributor to Lung Carcinogenesis and a New Therapeutic Target

2013 ◽  
pp. e295-e300
Author(s):  
Rosalyn A. Juergens ◽  
Charles M. Rudin
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Early Stage ◽  
Single Agent ◽  
Objective Response ◽  
Gene Promoter ◽  
Epigenetic Therapy ◽  
Lung Carcinogenesis

Carcinogenesis is driven by a combination of genetic and epigenetic abnormalities. Aberrancies in gene promoter methylation patterns and histone acetylation are associated with silencing of tumor suppressor genes in lung cancer and other solid tumors. Identification of key epigenetic modifications has been shown to be prognostic in early-stage non-small cell lung cancer. Previous clinical trials aimed at modifying the epigenome with single-agent demethylating agents or histone deacetylase inhibitors given at maximally tolerated doses have provided disappointing results. A recent clinical trial using a combination of a demethylating agent and a histone deacetylase inhibitor at “epigenetically targeted” doses concomitantly has shown promising results, including a patient with a complete objective response. Biomarkers associated with this clinical trial suggest that patients who undergo robust demethylation, as detected in the peripheral blood after a month on treatment, identifies those who gain the most benefit from this novel treatment strategy. Based on observations of unusually durable responses to subsequent therapy after administration of combined epigenetic therapy, epigenetic therapy may also play a role in “priming” patients to better respond to standard cytotoxic therapy or immunotherapy. This manuscript will review the data on the role of epigenetics in lung cancer and the history of epigenetic treatments in lung cancer spanning over the last 40 years.

DNA Methylation Analysis of 807 Genes in Chronic Myeloid Leukemia and Acute Promyelocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2122-2122 ◽  
Author(s):  
Hyang-Min Byun ◽  
Shahrooz Eshaghian ◽  
Jia Yi Jiang ◽  
Si Ho Choi ◽  
John Soussa ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cpg Island ◽  
Blast Crisis ◽  
Bimodal Distribution ◽  
Epigenetic Therapy ◽  
Dna Hypermethylation ◽  
Cpg Sites ◽  
Genetic Translocation ◽  
Methylator Phenotype ◽  
Hypermethylated Genes

Abstract DNA methylation changes are a common finding in leukemia, and hypermethylation of CpG island promoters is associated with aberrant gene silencing. Some abnormal cancer related methylation changes have been associated with clinical phenotype including pathologic features, prognosis, and treatment response. However, other DNA methylation changes do not appear to have phenotypic consequences and may reflect a stochastic event or a downstream event of tumorogenesis, such as the CpG island methylator phenotype (CIMP). In order to obtain a better understanding of the DNA methylation changes found in leukemia we analyzed 18 acute promyelocytic leukemia (APL) and 36 chronic myeloid leukemia (CML) patients. We specifically chose to study APL and CML as these leukemia are initiated by specific genetic translocation events, t(15:17) and t(9:22) respectively. To measure the DNA methylation status, we used the GoldenGate Assay for Methylation and BeadArray technology from Illumina, Inc. The Standard Methylation Cancer Panel I from Illumina interrogates 1505 CpG sites, selected from 807 genes (231 genes contain one CpG site per gene, 463 genes contain two CpG sites and 114 genes have three or more CpG sites). In our study we found 142 and 269 genes that were hypermethylated in CML and APL. 31 genes were uniquely hypermethylated in CML, 158 genes were hypermethylated only in APL, and 111 genes were hypermethylated in both leukemias. There was a unique pattern of hypermethylated genes in each cancer; such there was a high concordance of hypermethylated genes within each leukemia type. These data suggest that the epigenetic events were a result of the genetic translocation BCR/ABL or PML/RARα (associated with chromosomal aberrations t(9:22) or t(15:17)) that initiates these leukemias. Analysis of the number of hypermethylated genes in these two leukemias showed a bimodal distribution suggestive of CIMP, however, closer examination showed that this bimodal distribution could be attributed to the two different types of leukemia. APL patients had mean of 280 genes hypermethylated while CML patients only had a mean of 193 genes hypermethylated. APL had a stronger methylator phenotype than CML for the loci studied, which underscores the possible relationship of CIMP to a genetic phenotype. Subset analysis of our CML samples by chronic phase (23 patients), accelerated phase (5 patients), and blast crisis (8 patients) revealed 42 genes that became hypermethylated with progression of CML. It is possible that hypermethylation of these genes are clinically important in the leukemia phenotype, and maybe targets for epigenetic therapy. We examined the DNA methylation changes induced by the DNA methylation inhibitor, azacitidine, in a patient with blast crisis CML and refractory to imatinib mesylate therapy. Azacitidine could reverse the aberrant hypermethylation associated with progression of CML to blast crisis and supports the use of this drug as an epigenetic therapy. Our data show that the majority of DNA hypermethylation events in leukemia are dependent on genetic events, but there is a subset of DNA hypermethylation events that are involved in the progression of leukemia and may be therapeutically reversed by DNA methylation inhibitors.

scholarly journals Oligoamine analogues in combination with 2-difluoromethylornithine synergistically induce re-expression of aberrantly silenced tumour-suppressor genes

2012 ◽  
Vol 442 (3) ◽  
pp. 693-701 ◽  
Author(s):  
Yu Wu ◽  
Nora Steinbergs ◽  
Tracy Murray-Stewart ◽  
Laurence J. Marton ◽  
Robert A. Casero
Keyword(s):  
Colorectal Cancer ◽  
Transcriptional Activation ◽  
Cpg Island ◽  
Amine Oxidase ◽  
Synergistic Effects ◽  
Gene Promoter ◽  
Tumour Suppressor ◽  
Epigenetic Therapy ◽  
Tumour Suppressor Genes ◽  
Suppressor Genes

Epigenetic gene silencing is an important mechanism in the initiation and progression of cancer. Abnormal DNA CpG island hypermethylation and histone modifications are involved in aberrant silencing of tumour-suppressor genes. LSD1 (lysine-specific demethylase 1) was the first enzyme identified to specifically demethylate H3K4 (Lys4 of histone H3). Methylated H3K4 is an important mark associated with transcriptional activation. The flavin adenine dinucleotide-binding amine oxidase domain of LSD1 is homologous with two polyamine oxidases, SMO (spermine oxidase) and APAO (N1-acetylpolyamine oxidase). We have demonstrated previously that long-chain polyamine analogues, the oligoamines, are inhibitors of LSD1. In the present paper we report the synergistic effects of specific oligoamines in combination with DFMO (2-difluoromethylornithine), an inhibitor of ornithine decarboxylase, in human colorectal cancer cells. DFMO treatment depletes natural polyamines and increases the uptake of exogenous polyamines. The combination of oligoamines and DFMO results in a synergistic re-expression of aberrantly silenced tumour-suppressor genes, including SFRP2 (secreted frizzled-related protein 2), which encodes a Wnt signalling pathway antagonist and plays an anti-tumorigenic role in colorectal cancer. The treatment-induced re-expression of SFRP2 is associated with increased H3K4me2 (di-methyl H3K4) in the gene promoter. The combination of LSD1-inhibiting oligoamines and DFMO represents a novel approach to epigenetic therapy of cancer.

scholarly journals Hypermethylation involved in DNA profiles of lung cancer specific tumour suppressor genes and epigenetic modification caused by an ultra-highly diluted homeopathic drug, Condurango 30C, in vitro and in vivo

2021 ◽  
Vol 13 (47) ◽  
pp. 99-99
Author(s):  
Anisur Rahman Khuda-Bukhsh ◽  
Sourav Sidkar
Keyword(s):  
Lung Cancer ◽  
Dna Methylation ◽  
Epigenetic Modification ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Dna Hypermethylation ◽  
Suppressor Genes ◽  
Homeopathic Drug

Background and objectives: DNA hyper-methylation is an important aspect involved in carcinogenesis and cancer progression, which affects mainly CpG islands of DNA and causes inactivation of tumour suppressor genes. Therefore DNA hypermethylation status of the genomic DNA in both the transformed cancerous cell lines and in carcinogen-induced lung cancer was ascertained by analysis of expressions of certain major lung cancer specific tumour suppressor genes. The other objective was to examine if ultra highly diluted homeopathic drug, Condurango 30C, had ability to modulate DNA methylation. Methods: DNA methylation activity, if any, has been ascertained in H460-NSCLC cells in vitro and in BaP-induced lung cancer of rats in vivo, in respect of tumour suppressor genes like p15, p16, p18 and p53 by using PCR-SSCP analyses. The ability of modulation of DNA methylation, if any, by Condurango 30C was also verified against placebo control in a blinded manner. Results: Condurango 30C-treated DNA showed significant decrease in band-intensity of p15 and p53 genes especially in methylated condition, in vitro, at the IC50 dose (2.43µl/100µl). SSCP analysis of p15 and p53 genes in Condurango 30C-treated DNA also supported ability of Condurango 30C to modulate methylation state, in vitro. Inhibition of p15 hypermethylation was observed after post cancer treatment of rat with Condurango 30C. SSCP results gave a better indication of differences in band-position and single strand separation of p15 and p53 in Condurango 30C treated samples. Conclusion: Condurango 30C could trigger epigenetic modification in lung cancer via modulation of DNA hypermethylation but placebos could not.

scholarly journals Suppression of m6A mRNA modification by DNA hypermethylated ALKBH5 aggravates the oncological behavior of KRAS mutation/LKB1 loss lung cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Donghong Zhang ◽  
Jinfeng Ning ◽  
Imoh Okon ◽  
Xiaoxu Zheng ◽  
Ganesh Satyanarayana ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epigenetic Modification ◽  
Suppressor Gene ◽  
Ctcf Binding ◽  
Binding Motif ◽  
Loss Of Function ◽  
Dna Hypermethylation ◽  
Lung Cancer Patients ◽  
Lkb1 Tumor Suppressor ◽  
And Migration

AbstractOncogenic KRAS mutations combined with the loss of the LKB1 tumor-suppressor gene (KL) are strongly associated with aggressive forms of lung cancer. N6-methyladenosine (m6A) in mRNA is a crucial epigenetic modification that controls cancer self-renewal and progression. However, the regulation and role of m6A modification in this cancer are unclear. We found that decreased m6A levels correlated with the disease progression and poor survival for KL patients. The correlation was mediated by a special increase in ALKBH5 (AlkB family member 5) levels, an m6A demethylase. ALKBH5 gain- or loss-of function could effectively reverse LKB1 regulated cell proliferation, colony formation, and migration of KRAS-mutated lung cancer cells. Mechanistically, LKB1 loss upregulated ALKBH5 expression by DNA hypermethylation of the CTCF-binding motif on the ALKBH5 promoter, which inhibited CTCF binding but enhanced histone modifications, including H3K4me3, H3K9ac, and H3K27ac. This effect could successfully be rescued by LKB1 expression. ALKBH5 demethylation of m6A stabilized oncogenic drivers, such as SOX2, SMAD7, and MYC, through a pathway dependent on YTHDF2, an m6A reader protein. The above findings were confirmed in clinical KRAS-mutated lung cancer patients. We conclude that loss of LKB1 promotes ALKBH5 transcription by a DNA methylation mechanism, reduces m6A modification, and increases the stability of m6A target oncogenes, thus contributing to aggressive phenotypes of KRAS-mutated lung cancer.

scholarly journals The role of exosomes in lung cancer metastasis and clinical applications: an updated review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lei Yin ◽  
Xiaotian Liu ◽  
Xuejun Shao ◽  
Tao Feng ◽  
Jun Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Cancer Cell ◽  
Cancer Metastasis ◽  
Value Assessment ◽  
Lung Carcinogenesis ◽  
Research Attention ◽  
Mesenchymal Transition ◽  
Lung Cancer Metastasis

AbstractLung cancer is the leading cause of cancer-associated deaths accounting for 24% of all cancer deaths. As a crucial phase of tumor progression, lung cancer metastasis is linked to over 70% of these mortalities. In recent years, exosomes have received increasing research attention in their role in the induction of carcinogenesis and metastasis in the lung. In this review, recent studies on the contribution of exosomes to lung cancer metastasis are discussed, particularly highlighting the role of lung tumor-derived exosomes in immune system evasion, epithelial-mesenchymal transition, and angiogenesis, and their involvement at both the pre-metastatic and metastatic phases. The clinical application of exosomes as therapeutic drug carriers, their role in antitumor drug resistance, and their utility as predictive biomarkers in diagnosis and prognosis are also presented. The metastatic activity, a complex multistep process of cancer cell invasion, survival in blood vessels, attachment and subsequent colonization of the host's organs, is integrated with exosomal effects. Exosomes act as functional mediating factors in cell–cell communication, influencing various steps of the metastatic cascade. To this end, lung cancer cell-derived exosomes enhance cell proliferation, angiogenesis, and metastasis, regulate drug resistance, and antitumor immune activities during lung carcinogenesis, and are currently being explored as an important component in liquid biopsy assessment for diagnosing lung cancer. These nano-sized extracellular vesicles are also being explored as delivery vehicles for therapeutic molecules owing to their unique properties of biocompatibility, circulatory stability, decreased toxicity, and tumor specificity. The current knowledge of the role of exosomes highlights an array of exosome-dependent pathways and cargoes that are ripe for exploiting therapeutic targets to treat lung cancer metastasis, and for predictive value assessment in diagnosis, prognosis, and anti-tumor drug resistance.

Role of sex hormones in lung cancer

2021 ◽  
pp. 153537022110196
Author(s):  
Nathalie Fuentes ◽  
Miguel Silva Rodriguez ◽  
Patricia Silveyra
Keyword(s):  
Lung Cancer ◽  
Sex Differences ◽  
Sex Hormones ◽  
Hormone Receptors ◽  
Occupational Exposures ◽  
Lung Carcinogenesis ◽  
Male And Female ◽  
Female Sex ◽  
Incidence And Mortality ◽  
Cancer Rates

Lung cancer represents the world’s leading cause of cancer deaths. Sex differences in the incidence and mortality rates for various types of lung cancers have been identified, but the biological and endocrine mechanisms implicated in these disparities have not yet been determined. While some cancers such as lung adenocarcinoma are more commonly found among women than men, others like squamous cell carcinoma display the opposite pattern or show no sex differences. Associations of tobacco product use rates, susceptibility to carcinogens, occupational exposures, and indoor and outdoor air pollution have also been linked to differential rates of lung cancer occurrence and mortality between sexes. While roles for sex hormones in other types of cancers affecting women or men have been identified and described, little is known about the influence of sex hormones in lung cancer. One potential mechanism identified to date is the synergism between estrogen and some tobacco compounds, and oncogene mutations, in inducing the expression of metabolic enzymes, leading to enhanced formation of reactive oxygen species and DNA adducts, and subsequent lung carcinogenesis. In this review, we present the literature available regarding sex differences in cancer rates, associations of male and female sex hormones with lung cancer, the influence of exogenous hormone therapy in women, and potential mechanisms mediated by male and female sex hormone receptors in lung carcinogenesis. The influence of biological sex on lung disease has recently been established, thus new research incorporating this variable will shed light on the mechanisms behind the observed disparities in lung cancer rates, and potentially lead to the development of new therapeutics to treat this devastating disease.

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