Epigenetic Research in Stem Cell Bioengineering—Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials

The epigenome denotes all the information related to gene expression that is not contained in the DNA sequence but rather results from chemical changes to histones and DNA. Epigenetic modifications act in a cooperative way towards the regulation of gene expression, working at the transcriptional or post-transcriptional level, and play a key role in the determination of phenotypic variations in cells containing the same genotype. Epigenetic modifications are important considerations in relation to anti-cancer therapy and regenerative/reconstructive medicine. Moreover, a range of clinical trials have been performed, exploiting the potential of epigenetics in stem cell engineering towards application in disease treatments and diagnostics. Epigenetic studies will most likely be the basis of future cancer therapies, as epigenetic modifications play major roles in tumour formation, malignancy and metastasis. In fact, a large number of currently designed or tested clinical approaches, based on compounds regulating epigenetic pathways in various types of tumours, employ these mechanisms in stem cell bioengineering.

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Regulation of gene expression during spermatogenesis at transcriptional level

Hereditas (Beijing) ◽

10.3724/sp.j.1005.2011.01300 ◽

2011 ◽

Vol 33 (12) ◽

pp. 1300-1307

Author(s):

Xiu-Jun ZHANG ◽

Mei-Ling LIU ◽

Meng-Chun JIA

Keyword(s):

Gene Expression ◽

Regulation Of Gene Expression ◽

Transcriptional Level

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Leveraging epigenetics to enhance the efficacy of immunotherapy

Clinical Epigenetics ◽

10.1186/s13148-021-01100-x ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Jonathan D. Licht ◽

Richard L. Bennett

Keyword(s):

Gene Expression ◽

Clinical Trials ◽

Antigen Presentation ◽

Tumor Cells ◽

Immune Evasion ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Epigenetic Modifications ◽

Main Body ◽

Epigenetic Mechanisms

Abstract Background Epigenetic mechanisms regulate chromatin accessibility patterns that govern interaction of transcription machinery with genes and their cis-regulatory elements. Mutations that affect epigenetic mechanisms are common in cancer. Because epigenetic modifications are reversible many anticancer strategies targeting these mechanisms are currently under development and in clinical trials. Main body Here we review evidence suggesting that epigenetic therapeutics can deactivate immunosuppressive gene expression or reprogram tumor cells to activate antigen presentation mechanisms. In addition, the dysregulation of epigenetic mechanisms commonly observed in cancer may alter the immunogenicity of tumor cells and effectiveness of immunotherapies. Conclusions Therapeutics targeting epigenetic mechanisms may be helpful to counter immune evasion and improve the effectiveness of immunotherapies.

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The cancer stem cell microenvironment and anti-cancer therapy

International Journal of Radiation Biology ◽

10.3109/09553000903242164 ◽

2009 ◽

Vol 85 (11) ◽

pp. 955-962 ◽

Cited By ~ 28

Author(s):

Veerander P. S. Ghotra ◽

Jordi C. Puigvert ◽

Erik H. J. Danen

Keyword(s):

Stem Cell ◽

Cancer Therapy ◽

Cancer Stem Cell ◽

Cell Microenvironment ◽

Anti Cancer

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Regulation of proton-translocating V-ATPases.

Journal of Experimental Biology ◽

10.1242/jeb.200.2.225 ◽

1997 ◽

Vol 200 (2) ◽

pp. 225-235 ◽

Cited By ~ 8

Author(s):

H Merzendorfer ◽

R Gräf ◽

M Huss ◽

W R Harvey ◽

H Wieczorek

Keyword(s):

Gene Expression ◽

Enzyme Activity ◽

Plasma Membranes ◽

Regulation Of Gene Expression ◽

Transcriptional Level ◽

Structural Domains ◽

Sh Groups ◽

Signalling Molecules ◽

Membrane Spanning ◽

Regulation Of Enzyme Activity

Vacuolar-type ATPases (V-ATPases) are proton-translocating enzymes that occur in the endomembranes of all eukaryotes and in the plasma membranes of many eukaryotes. They are multisubunit, heteromeric proteins composed of two structural domains, a peripheral, catalytic V1 domain and a membrane-spanning V0 domain. Both the multitude of locations and the heteromultimeric structure make it likely that the expression and the activity of V-ATPases are regulated in various ways. Regulation of gene expression encompasses control of transcription as well as control at the post-transcriptional level. Regulation of enzyme activity encompasses many diverse mechanisms such as disassembly/reassembly of V1 and V0 domains, oxidation of SH groups, control by activator and inhibitor proteins or by small signalling molecules, and sorting of the holoenzyme or its subunits to target membranes.

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Emodin Attenuates Pathological Cardiac Hypertrophy by Regulating Gene Expression Through Acetyl-histone-mediated Actions (P06-036-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.p06-036-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Levi Evans ◽

Bradley Ferguson

Keyword(s):

Gene Expression ◽

Cardiac Hypertrophy ◽

Histone Acetylation ◽

Regulation Of Gene Expression ◽

Epigenetic Modifications ◽

Neonatal Rat ◽

Heart Health ◽

Hdac Activity ◽

Pathological Cardiac Hypertrophy ◽

Epigenetic Regulators

Abstract Objectives Epigenetic modifications regulate gene expression without changing DNA sequence and are reversible, highlighting their therapeutic potential for heart failure. Recent evidence suggests that food compounds can reverse these stress-induced epigenetic modifications, yet few studies have characterized their role as epigenetic regulators of heart health. Our objective tested the hypothesis that Emodin, an Antraquinone found in rhubarb, blocked pathological cardiac hypertrophy via acetyl-histone-mediated gene expression changes. Methods To test this hypothesis, neonatal rat ventricular myocytes (NRVMs) were stimulated with phenylephrine (PE, 10 μM) to induce receptor-mediated pathological cardiac hypertrophy in the absence or presence of vehicle control or Emodin (10 μM) for 48 hours. Cells were subsequently 1) fixed for immunostaining and cell size quantification, 2) lysed for protein to assess HDAC activity and histone acetylation or 3) lysed for RNA to analyze transcriptome–wide changes in gene expression. A minimum of three experiments with an n = 3/group was performed and data quantified. One-way ANOVA with Tukey's post-hoc was performed unless otherwise specified. p < 0.05 was considered significant. Results Emodin significantly blocked PE-induced hypertrophy. Emodin significantly inhibited HDAC activity concomitant to increased histone acetylation. Lastly, Emodin reversed stress-induced changes in gene expression. Conclusions Our data suggest that Emodin inhibited pathological cardiac hypertrophy via acetyl-histone dependent regulation of gene expression. While animal studies are currently underway to examine the epigenetic actions for emodin in cardiac protection, our results support the role for food compounds like Emodin as epigenetic regulators of heart health. Funding Sources This work is supported by the USDA NIFA (Hatch-NEV00727), the Dennis Meiss & Janet Ralston Fund for Nutri-epigenetic Research and by the National Institute for General Medical Sciences (NIGMS) of the NIH (P20 GM130459) to B.S.F. Core facilities used for Research were supported by NIGMS of the NIH (P20 GM103554).

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Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment

International Journal of Molecular Sciences ◽

10.3390/ijms21207575 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7575 ◽

Cited By ~ 1

Author(s):

Shruti S. Sawant ◽

Suyash M. Patil ◽

Vivek Gupta ◽

Nitesh K. Kunda

Keyword(s):

Cancer Therapy ◽

Cancer Treatment ◽

Treatment Options ◽

Current Treatment ◽

Genetically Engineered ◽

Cancer Therapies ◽

Anti Cancer ◽

Tumor Environment ◽

Systemic Side Effects ◽

Hypoxic Tumor

Conventional anti-cancer therapy involves the use of chemical chemotherapeutics and radiation and are often non-specific in action. The development of drug resistance and the inability of the drug to penetrate the tumor cells has been a major pitfall in current treatment. This has led to the investigation of alternative anti-tumor therapeutics possessing greater specificity and efficacy. There is a significant interest in exploring the use of microbes as potential anti-cancer medicines. The inherent tropism of the bacteria for hypoxic tumor environment and its ability to be genetically engineered as a vector for gene and drug therapy has led to the development of bacteria as a potential weapon against cancer. In this review, we will introduce bacterial anti-cancer therapy with an emphasis on the various mechanisms involved in tumor targeting and tumor suppression. The bacteriotherapy approaches in conjunction with the conventional cancer therapy can be effective in designing novel cancer therapies. We focus on the current progress achieved in bacterial cancer therapies that show potential in advancing existing cancer treatment options and help attain positive clinical outcomes with minimal systemic side-effects.

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Targeting ERK-Hippo Interplay in Cancer Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms21093236 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3236 ◽

Cited By ~ 2

Author(s):

Karel Vališ ◽

Petr Novák

Keyword(s):

Cancer Therapy ◽

Signaling Pathways ◽

Signaling Pathway ◽

Cross Talk ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Cancer Therapies ◽

Anti Cancer ◽

Targeted Inhibition

Extracellular signal-regulated kinase (ERK) is a part of the mitogen-activated protein kinase (MAPK) signaling pathway which allows the transduction of various cellular signals to final effectors and regulation of elementary cellular processes. Deregulation of the MAPK signaling occurs under many pathological conditions including neurodegenerative disorders, metabolic syndromes and cancers. Targeted inhibition of individual kinases of the MAPK signaling pathway using synthetic compounds represents a promising way to effective anti-cancer therapy. Cross-talk of the MAPK signaling pathway with other proteins and signaling pathways have a crucial impact on clinical outcomes of targeted therapies and plays important role during development of drug resistance in cancers. We discuss cross-talk of the MAPK/ERK signaling pathway with other signaling pathways, in particular interplay with the Hippo/MST pathway. We demonstrate the mechanism of cell death induction shared between MAPK/ERK and Hippo/MST signaling pathways and discuss the potential of combination targeting of these pathways in the development of more effective anti-cancer therapies.

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Human pluripotent stem cell-derived natural killer cells for anti-cancer therapy

Experimental Hematology ◽

10.1016/j.exphem.2016.06.023 ◽

2016 ◽

Vol 44 (9) ◽

pp. S31

Author(s):

Dan Kaufman

Keyword(s):

Stem Cell ◽

Natural Killer Cells ◽

Cancer Therapy ◽

Natural Killer ◽

Pluripotent Stem Cell ◽

Human Pluripotent Stem Cell ◽

Killer Cells ◽

Anti Cancer

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Epigenetics and maternal nutrition: nature v. nurture

Proceedings of The Nutrition Society ◽

10.1017/s0029665110003988 ◽

2010 ◽

Vol 70 (1) ◽

pp. 73-81 ◽

Cited By ~ 69

Author(s):

Rebecca Simmons

Keyword(s):

Gene Expression ◽

Maternal Nutrition ◽

Current Knowledge ◽

Regulation Of Gene Expression ◽

Epigenetic Modifications ◽

Epigenetic Gene Regulation ◽

Diabetes And Obesity

Under- and over-nutrition during pregnancy has been linked to the later development of diseases such as diabetes and obesity. Epigenetic modifications may be one mechanism by which exposure to an altered intrauterine milieu or metabolic perturbation may influence the phenotype of the organism much later in life. Epigenetic modifications of the genome provide a mechanism that allows the stable propagation of gene expression from one generation of cells to the next. This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodelling and histone modifications play key roles in adipogenesis and the development of obesity. Epigenetic modifications affecting processes important to glucose regulation and insulin secretion have been described in the pancreatic β-cells and muscle of the intrauterine growth-retarded offspring, characteristics essential to the pathophysiology of type-2 diabetes. Epigenetic regulation of gene expression contributes to both adipocyte determination and differentiation in in vitro models. The contributions of histone acetylation, histone methylation and DNA methylation to the process of adipogenesis in vivo remain to be evaluated.

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