• Molecules and Cells
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• v.42 no.7
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• pp.530-545
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• 2019

Tumor cells can vary epigenetically during ionizing irradiation (IR) treatment. These epigenetic variegations can influence IR response and shape tumor aggressiveness. However, epigenetic disturbance of histones after IR, implicating in IR responsiveness, has been elusive. Here, we investigate whether altered histone modification after IR can influence radiation responsiveness. The oncogenic CXCL12 mRNA and protein were more highly expressed in residual cancer cells from a hepatoma heterotopic murine tumor microenvironment and coculture of human hepatoma Huh7 and normal IMR90 cells after radiation. H3K4 methylation was also enriched and H3K9 methylation was decreased at its promoter region. Accordingly, invasiveness and the subpopulation of aggressive $CD133^+/CD24^-$ cells increased after IR. Histone demethylase inhibitor IOX1 attenuated CXCL12 expression and the malignant subpopulation, suggesting that responses to IR can be partially mediated via histone modifications. Taken together, radiation-induced histone alterations at the CXCL12 promoter in hepatoma cells are linked to CXCL12 upregulation and increased aggressiveness in the tumor microenvironment.

• Journal of Life Science
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• v.25 no.6
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• pp.724-731
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• 2015

Mesenchymal stem cells (MSCs) are characterized by their multipotency capacity, which allows them to differentiate into diverse cell types (bone, cartilage, fat, tendon, and neuron-like cells) and secrete a variety of trophic factors (ANG, FGF-2, HGF, IGF-1, PIGF, SDF-1α, TGF-β, and VEGF). MSCs can be easily isolated from human bone-marrow, fat, and umbilical-cord tissues. These features indicate that MSCs might be of use in stem-cell therapy. However, MSCs undergo cellular senescence during long-term expansion, and this is accompanied by functional declines in stem-cell potency. In the human body, because of their senescence and declines in their microenvironmental niches stem cells fail to maintain tissue homeostasis, and as a result, senescent cells accumulate in tissues. This can lead to age-related diseases, including degenerative disorders and cancers. Recent studies suggest that the number of histone modifications to stem cells’ genomes and aberrant alterations to their DNA methylation increase as stem cells progress into senescence. These epigenetic alterations have been partly reversed with treatments in which DNA methyltransferase (DNMT) inhibitors or histone deacetylase (HDAC) inhibitors are introduced into replicative senescent-MSCs. This review focuses on epigenetic alteration in replicative senescent-MSCs and explains how epigenetic modifications are widely associated with stem-cell senescences such as differentiation, proliferation, migration, calcium signaling, and apoptosis.

• Molecules and Cells
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• v.41 no.5
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• pp.381-389
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• 2018

ARF is a tumor suppressor protein that has a pivotal role in the prevention of cancer development through regulating cell proliferation, senescence, and apoptosis. As a factor that induces senescence, the role of ARF as a tumor suppressor is closely linked to the p53-MDM2 axis, which is a key process that restrains tumor formation. Thus, many cancer cells either lack a functional ARF or p53, which enables them to evade cell oncogenic stress-mediated cycle arrest, senescence, or apoptosis. In particular, the ARF gene is a frequent target of genetic and epigenetic alterations including promoter hyper-methylation or gene deletion. However, as many cancer cells still express ARF, pathways that negatively modulate transcriptional or post-translational regulation of ARF could be potentially important means for cancer cells to induce cellular proliferation. These recent findings of regulators affecting ARF protein stability along with its low levels in numerous human cancers indicate the significance of an ARF post-translational mechanism in cancers. Novel findings of regulators stimulating or suppressing ARF function would provide new therapeutic targets to manage cancer- and senescence-related diseases. In this review, we present the current knowledge on the regulation and alterations of ARF expression in human cancers, and indicate the importance of regulators of ARF as a prognostic marker and in potential therapeutic strategies.

• Genomics & Informatics
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• v.17 no.4
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• pp.38.1-38.6
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• 2019

DNA methylation is a relatively stable epigenetic modification that can regulate and stabilize gene expression patterns and hence establish cell identity. Because metabolic intermediates are key factors of DNA methylation and demethylation, perturbations in metabolic homeostasis can trigger alterations in cell-specific patterns of DNA methylation and contribute to disease development, including type 2 diabetes (T2D). During the past decade, genome-wide DNA methylation studies of T2D have expanded our knowledge of the molecular mechanisms underlying T2D. This review summarizes case-control studies of the DNA methylome of T2D and discusses DNA methylation as both a cause and consequence of T2D. Therefore, DNA methylation has potential as a promising T2D biomarker that can be applied to the development of therapeutic strategies for T2D.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.6
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• pp.2445-2452
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• 2012

RNA interference has created a breakthrough in gene silencing technology and there is now much debate on the successful usage of RNAi based methods in treating a number of debilitating diseases. Cancer is often regarded as a result of mutations in genomic DNA resulting in faulty gene expression. The occurrence of cancer can also be influenced by epigenetic irregularities in the chromatin structure which leads to alterations and mutations in DNA resulting in cancer cell formation. A number of therapeutic approaches have been put forth to treat cancer. Anti cancer therapy often involves chemotherapy targeting all the cells in common, whereby both cancer cells as well as normal cells get affected. Hence RNAi technology has potential to be a better therapeutic agent as it is possible to deactivate molecular targets like specific mutant genes. This review highlights the successful use of RNAi inducers against different types of cancer, thereby paving the way for specific therapeutic medicines.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.4
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• pp.1595-1608
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• 2016

Triple-negative breast cancer (TNBC) is defined as a type of breast carcinoma that is negative for expression of oestrogene and progesterone hormone receptors (ER, PR) and HER2. This form of breast cancer is marked by its aggressiveness, low survival rate and lack of specific therapies. Recently, important molecular characteristics of TNBC have been highlighted and led to the identification of some biomarkers that could be used in diagnosis, as therapeutic targets or to assess the prognosis. In this review, we summarize recent progress in TNBC research focusing on the genetic and epigenetic alterations of TNBC and the potential use of these biomarkers in the targeted therapy for better management of TNBC.

• Molecules and Cells
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• v.43 no.2
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• pp.176-181
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• 2020

The RUNX transcription factors serve as master regulators of development and are frequently dysregulated in human cancers. Among the three family members, RUNX3 is the least studied, and has long been considered to be a tumor-suppressor gene in human cancers. This idea is mainly based on the observation that RUNX3 is inactivated by genetic/epigenetic alterations or protein mislocalization during the initiation of tumorigenesis. Recently, this paradigm has been challenged, as several lines of evidence have shown that RUNX3 is upregulated over the course of tumor development. Resolving this paradox and understanding how a single gene can exhibit both oncogenic and tumor-suppressive properties is essential for successful drug targeting of RUNX. We propose a simple explanation for the duality of RUNX3: p53 status. In this model, p53 deficiency causes RUNX3 to become an oncogene, resulting in aberrant upregulation of MYC.

• BMB Reports
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• v.57 no.3
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• pp.135-142
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• 2024

DNA methylation is one of the most extensively studied epigenetic regulatory mechanisms, known to play crucial roles in various organisms. It has been implicated in the regulation of gene expression and chromatin changes, ranging from global alterations during cell state transitions to locus-specific modifications. 5-hydroxymethylcytosine (5hmC) is produced by a major oxidation, from 5-methylcytosine (5mC), catalyzed by the ten-eleven translocation (TET) enzymes, and is gradually being recognized for its significant role in genome regulation. With the development of state-of-the-art experimental techniques, it has become possible to detect and distinguish 5mC and 5hmC at base resolution. Various techniques have evolved, encompassing chemical and enzymatic approaches, as well as third-generation sequencing techniques. These advancements have paved the way for a thorough exploration of the role of 5hmC across a diverse array of cell types, from embryonic stem cells (ESCs) to various differentiated cells. This review aims to comprehensively report on recent techniques and discuss the emerging roles of 5hmC.

• International Journal of Stem Cells
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• v.17 no.1
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• pp.1-14
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• 2024

The clustered regularly interspaced short palindromic repeats (CRISPR) system, a rapidly advancing genome editing technology, allows DNA alterations into the genome of organisms. Gene editing using the CRISPR system enables more precise and diverse editing, such as single nucleotide conversion, precise knock-in of target sequences or genes, chromosomal rearrangement, or gene disruption by simple cutting. Moreover, CRISPR systems comprising transcriptional activators/repressors can be used for epigenetic regulation without DNA damage. Stem cell DNA engineering based on gene editing tools has enormous potential to provide clues regarding the pathogenesis of diseases and to study the mechanisms and treatments of incurable diseases. Here, we review the latest trends in stem cell research using various CRISPR/Cas technologies and discuss their future prospects in treating various diseases.

• Journal of Photoscience
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• v.9 no.2
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• pp.221-224
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• 2002

Carcinogenesis can be theoretically divided to intiation step and promotion step. Intiation associates with genetic alterations including p53 tumor suppressor gene and ras oncogene. Promotion involves in clonal expansion of of an initiated cell by epigenetic mechanism, mainly through signal transduction and gene expression. Ultraviolet light (UV) acts as both initiator and promoter. Initiation is closely related with DNA damage induced by UV, including cyclobutane pyrimidine dimers, (6-4) photoproducts and 8-hydroxy-2'-deoxyguanosine. Cyclobutane pyrimidine dimers and (6-4) photoproducts are directly induced by UV, while 8-hydroxy-2'-deoxyguanosine is induced indirectly by the reactive oxygen species. Because initiation is an irreversal genetic event, while promotion is a reversal and epigenetic event, to know the molecular mechanisms of tumor promotion in UV-carcinogenesis is crucial to develop preventive medicine and suppress UV-carcinogenesis. Because ROS is also involved in signal transduction of the cell, anti-oxidant could be the good candidate of anti-promoting agent. Here, we describe the suppressive effect of UV-carcinogenesis by various anti-oxidant including olive oil. In addition, we discuss about the mechanism of UVB-induced expression of cyclooxygenase-2, which might be a representative molecule involved in promotion of UV-carcinogenesis.