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12 pages, 4116 KiB

Open AccessArticle

Epigenetic Modifier SETD8 as a Therapeutic Target for High-Grade Serous Ovarian Cancer

by Miku Wada, Asako Kukita, Kenbun Sone, Ryuji Hamamoto, Syuzo Kaneko, Masaaki Komatsu, Yu Takahashi, Futaba Inoue, Machiko Kojima, Harunori Honjoh, Ayumi Taguchi, Tomoko Kashiyama, Yuichiro Miyamoto, Michihiro Tanikawa, Tetsushi Tsuruga, Mayuyo Mori-Uchino, Osamu Wada-Hiraike, Yutaka Osuga and Tomoyuki Fujii

Biomolecules 2020, 10(12), 1686; https://doi.org/10.3390/biom10121686 - 16 Dec 2020

Cited by 13 | Viewed by 2960

Abstract

The histone methyltransferase SETD8, which methylates the lysine 20 of histone H4 (H4K20), is reportedly involved in human carcinogenesis along with nonhistone proteins such as p53. However, its expression profiles and functions in the context of high-grade serous ovarian carcinoma (HGSOC) are still [...] Read more.

The histone methyltransferase SETD8, which methylates the lysine 20 of histone H4 (H4K20), is reportedly involved in human carcinogenesis along with nonhistone proteins such as p53. However, its expression profiles and functions in the context of high-grade serous ovarian carcinoma (HGSOC) are still unknown. The purpose of this study was to investigate the role of SETD8 in HGSOC. We performed quantitative real-time PCR and immunohistochemistry to detect the expression of SETD8 in HGSOC samples and normal ovarian specimens. Then, we assessed the effect of the inhibition of SETD8 expression using small interfering RNA (siRNA) and a selective inhibitor (UNC0379) on cell proliferation and apoptosis in HGSOC cells. The expression of SETD8 was significantly upregulated in clinical ovarian cancer specimens compared to that in the corresponding normal ovary. In addition, suppression of SETD8 expression in HGSOC cells with either siRNA or UNC0379 resulted in reduced levels of H4K20 monomethylation, inhibition of cell proliferation, and induction of apoptosis. Furthermore, UNC0379 showed a long-term antitumor effect against HGSOC cells, as demonstrated by colony-formation assays. SETD8 thus constitutes a promising therapeutic target for HGSOC, warranting further functional studies. Full article

(This article belongs to the Special Issue Epigenetics in Cancer)

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19 pages, 1585 KiB

Open AccessArticle

AP-TSS: A New Method for the Analysis of RNA Expression from Particular and Challenging Transcription Start Sites

by Gabriel Le Berre, Virginie Hossard, Jean-Francois Riou and Anne-Laure Guieysse-Peugeot

Biomolecules 2020, 10(6), 827; https://doi.org/10.3390/biom10060827 - 28 May 2020

Cited by 1 | Viewed by 3120

Abstract

Alternative promoter usage involved in the regulation of transcription, splicing, and translation contributes to proteome diversity and is involved in a large number of diseases, in particular, cancer. Epigenetic mechanisms and cis regulatory elements are involved in alternative promoter activity. Multiple transcript isoforms [...] Read more.

Alternative promoter usage involved in the regulation of transcription, splicing, and translation contributes to proteome diversity and is involved in a large number of diseases, in particular, cancer. Epigenetic mechanisms and cis regulatory elements are involved in alternative promoter activity. Multiple transcript isoforms can be produced from a gene, due to the initiation of transcription at different transcription start sites (TSS). These transcripts may not have regions that allow discrimination during RT-qPCR, making quantification technically challenging. This study presents a general method for the relative quantification of a transcript synthesized from a particular TSS that we called AP-TSS (analysis of particular TSS). AP-TSS is based on the specific elongation of the cDNA of interest, followed by its quantification by qPCR. As proof of principle, AP-TSS was applied to two non-coding RNA: telomeric repeat-containing RNAs (TERRA) from a particular subtelomeric TSS, and Alu transcripts. The treatment of cells with a DNA methylation inhibitor was associated with a global increase of the total TERRA level, but the TERRA expression from the TSS of interest did not change in HT1080 cells, and only modestly increased in HeLa cells. This result suggests that TERRA upregulation induced by global demethylation of the genome is mainly due to activation from sites other than this particular TSS. For Alu RNA, the signal obtained by AP-TSS is specific for the RNA Polymerase III-dependent Alu transcript. In summary, our method provides a tool to study regulation of gene expression from a given transcription start site, in different conditions that could be applied to many genes. In particular, AP-TSS can be used to investigate the epigenetic regulation of alternative TSS usage that is of importance for the development of epigenetic-targeted therapies. Full article

(This article belongs to the Special Issue Epigenetics in Cancer)

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17 pages, 3758 KiB

Open AccessCommunication

Genome-Wide Open Chromatin Methylome Profiles in Colorectal Cancer

by Muhiddin Ishak, Rashidah Baharudin, Isa Mohamed Rose, Ismail Sagap, Luqman Mazlan, Zairul Azwan Mohd Azman, Nadiah Abu, Rahman Jamal, Learn-Han Lee and Nurul Syakima Ab Mutalib

Biomolecules 2020, 10(5), 719; https://doi.org/10.3390/biom10050719 - 05 May 2020

Cited by 13 | Viewed by 3137

Abstract

The methylome of open chromatins was investigated in colorectal cancer (CRC) to explore cancer-specific methylation and potential biomarkers. Epigenome-wide methylome of open chromatins was studied in colorectal cancer tissues using the Infinium DNA MethylationEPIC assay. Differentially methylated regions were identified using the ChAMP [...] Read more.

The methylome of open chromatins was investigated in colorectal cancer (CRC) to explore cancer-specific methylation and potential biomarkers. Epigenome-wide methylome of open chromatins was studied in colorectal cancer tissues using the Infinium DNA MethylationEPIC assay. Differentially methylated regions were identified using the ChAMP Bioconductor. Our stringent analysis led to the discovery of 2187 significant differentially methylated open chromatins in CRCs. More hypomethylated probes were observed and the trend was similar across all chromosomes. The majority of hyper- and hypomethylated probes in open chromatin were in chromosome 1. Our unsupervised hierarchical clustering analysis showed that 40 significant differentially methylated open chromatins were able to segregate CRC from normal colonic tissues. Receiver operating characteristic analyses from the top 40 probes revealed several significant, highly discriminative, specific and sensitive probes such as OPLAH cg26256223, EYA4 cg01328892, and CCNA1 cg11513637, among others. OPLAH cg26256223 hypermethylation is associated with reduced gene expression in the CRC. This study reports many open chromatin loci with novel differential methylation statuses, some of which with the potential as candidate markers for diagnostic purposes. Full article

(This article belongs to the Special Issue Epigenetics in Cancer)

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16 pages, 2590 KiB

Open AccessEditor’s ChoiceArticle

Deregulation of the Histone Lysine-Specific Demethylase 1 Is Involved in Human Hepatocellular Carcinoma

by Sangchul Kim, Amina Bolatkan, Syuzo Kaneko, Noriko Ikawa, Ken Asada, Masaaki Komatsu, Shinya Hayami, Hidenori Ojima, Nobutsugu Abe, Hiroki Yamaue and Ryuji Hamamoto

Biomolecules 2019, 9(12), 810; https://doi.org/10.3390/biom9120810 - 01 Dec 2019

Cited by 20 | Viewed by 4218

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Given that the standard-of-care for advanced liver cancer is limited, there is an urgent need to develop a novel molecular targeted therapy [...] Read more.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Given that the standard-of-care for advanced liver cancer is limited, there is an urgent need to develop a novel molecular targeted therapy to improve therapeutic outcomes for HCC. In order to tackle this issue, we conducted functional analysis of the histone lysine-specific demethylase (LSD1) to explore the possibility that this enzyme acts as a therapeutic target in HCC. According to immunohistochemical analysis, 232 of 303 (77%) HCC cases showed positive staining of LSD1 protein, and its expression was correlated with several clinicopathological characteristics, such as female gender, AFP (alpha-fetoprotein) levels, and HCV (hepatitis C virus) infectious. The survival curves for HCC using the Kaplan–Meier method and the log-rank test indicate that positive LSD1 protein expression was significantly associated with decreased rates of overall survival (OS) and disease-free survival (DFS); the multivariate analysis indicates that LSD1 expression was an independent prognostic factor for both OS and DFS in patients with HCC. In addition, knockout of LSD1 using the CRISPR/Cas9 system showed a significantly lower number of colony formation units (CFUs) and growth rate in both SNU-423 and SNU-475 HCC cell lines compared to the corresponding control cells. Moreover, LSD1 knockout decreased cells in S phase of SNU-423 and SNU-475 cells with increased levels of H3K4me1/2 and H3K9me1/2. Finally, we identified the signaling pathways regulated by LSD1 in HCC, including the retinoic acid (RA) pathway. Our findings imply that deregulation of LSD1 can be involved in HCC; further studies may explore the usefulness of LSD1 as a therapeutic target of HCC. Full article

(This article belongs to the Special Issue Epigenetics in Cancer)

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16 pages, 2162 KiB

Open AccessArticle

Phylogenetic Analysis to Explore the Association Between Anti-NMDA Receptor Encephalitis and Tumors Based on microRNA Biomarkers

by Hsiuying Wang

Biomolecules 2019, 9(10), 572; https://doi.org/10.3390/biom9100572 - 05 Oct 2019

Cited by 13 | Viewed by 2796

Abstract

MicroRNA (miRNA) is a small non-coding RNA that functions in the epigenetics control of gene expression, which can be used as a useful biomarker for diseases. Anti-NMDA receptor (anti-NMDAR) encephalitis is an acute autoimmune disorder. Some patients have been found to have tumors, [...] Read more.

MicroRNA (miRNA) is a small non-coding RNA that functions in the epigenetics control of gene expression, which can be used as a useful biomarker for diseases. Anti-NMDA receptor (anti-NMDAR) encephalitis is an acute autoimmune disorder. Some patients have been found to have tumors, specifically teratomas. This disease occurs more often in females than in males. Most of them have a significant recovery after tumor resection, which shows that the tumor may induce anti-NMDAR encephalitis. In this study, I review microRNA (miRNA) biomarkers that are associated with anti-NMDAR encephalitis and related tumors, respectively. To the best of my knowledge, there has not been any research in the literature investigating the relationship between anti-NMDAR encephalitis and tumors through their miRNA biomarkers. I adopt a phylogenetic analysis to plot the phylogenetic trees of their miRNA biomarkers. From the analyzed results, it may be concluded that (i) there is a relationship between these tumors and anti-NMDAR encephalitis, and (ii) this disease occurs more often in females than in males. This sheds light on this issue through miRNA intervention. Full article

(This article belongs to the Special Issue Epigenetics in Cancer)

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Review

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18 pages, 1057 KiB

Open AccessReview

The Role of H3K4 Trimethylation in CpG Islands Hypermethylation in Cancer

by Giuseppe Zardo

Biomolecules 2021, 11(2), 143; https://doi.org/10.3390/biom11020143 - 22 Jan 2021

Cited by 10 | Viewed by 3184

Abstract

CpG methylation in transposons, exons, introns and intergenic regions is important for long-term silencing, silencing of parasitic sequences and alternative promoters, regulating imprinted gene expression and determining X chromosome inactivation. Promoter CpG islands, although rich in CpG dinucleotides, are unmethylated and remain so [...] Read more.

CpG methylation in transposons, exons, introns and intergenic regions is important for long-term silencing, silencing of parasitic sequences and alternative promoters, regulating imprinted gene expression and determining X chromosome inactivation. Promoter CpG islands, although rich in CpG dinucleotides, are unmethylated and remain so during all phases of mammalian embryogenesis and development, except in specific cases. The biological mechanisms that contribute to the maintenance of the unmethylated state of CpG islands remain elusive, but the modification of established DNA methylation patterns is a common feature in all types of tumors and is considered as an event that intrinsically, or in association with genetic lesions, feeds carcinogenesis. In this review, we focus on the latest results describing the role that the levels of H3K4 trimethylation may have in determining the aberrant hypermethylation of CpG islands in tumors. Full article

(This article belongs to the Special Issue Epigenetics in Cancer)

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23 pages, 1846 KiB

Open AccessEditor’s ChoiceReview

Cell-Free DNA-Methylation-Based Methods and Applications in Oncology

by Francesca Galardi, Francesca De Luca, Dario Romagnoli, Chiara Biagioni, Erica Moretti, Laura Biganzoli, Angelo Di Leo, Ilenia Migliaccio, Luca Malorni and Matteo Benelli

Biomolecules 2020, 10(12), 1677; https://doi.org/10.3390/biom10121677 - 15 Dec 2020

Cited by 32 | Viewed by 8203

Abstract

Liquid biopsy based on cell-free DNA (cfDNA) enables non-invasive dynamic assessment of disease status in patients with cancer, both in the early and advanced settings. The analysis of DNA-methylation (DNAm) from cfDNA samples holds great promise due to the intrinsic characteristics of DNAm [...] Read more.

Liquid biopsy based on cell-free DNA (cfDNA) enables non-invasive dynamic assessment of disease status in patients with cancer, both in the early and advanced settings. The analysis of DNA-methylation (DNAm) from cfDNA samples holds great promise due to the intrinsic characteristics of DNAm being more prevalent, pervasive, and cell- and tumor-type specific than genomics, for which established cfDNA assays already exist. Herein, we report on recent advances on experimental strategies for the analysis of DNAm in cfDNA samples. We describe the main steps of DNAm-based analysis workflows, including pre-analytics of cfDNA samples, DNA treatment, assays for DNAm evaluation, and methods for data analysis. We report on protocols, biomolecular techniques, and computational strategies enabling DNAm evaluation in the context of cfDNA analysis, along with practical considerations on input sample requirements and costs. We provide an overview on existing studies exploiting cell-free DNAm biomarkers for the detection and monitoring of cancer in early and advanced settings, for the evaluation of drug resistance, and for the identification of the cell-of-origin of tumors. Finally, we report on DNAm-based tests approved for clinical use and summarize their performance in the context of liquid biopsy. Full article

(This article belongs to the Special Issue Epigenetics in Cancer)

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22 pages, 1526 KiB

Open AccessReview

Critical Roles of N⁶-Methyladenosine (m⁶A) in Cancer and Virus Infection

by Ken Asada, Amina Bolatkan, Ken Takasawa, Masaaki Komatsu, Syuzo Kaneko and Ryuji Hamamoto

Biomolecules 2020, 10(7), 1071; https://doi.org/10.3390/biom10071071 - 17 Jul 2020

Cited by 16 | Viewed by 4444

Abstract

Studies have shown that epigenetic abnormalities are involved in various diseases, including cancer. In particular, in order to realize precision medicine, the integrated analysis of genetics and epigenetics is considered to be important; detailed epigenetic analysis in the medical field has been becoming [...] Read more.

Studies have shown that epigenetic abnormalities are involved in various diseases, including cancer. In particular, in order to realize precision medicine, the integrated analysis of genetics and epigenetics is considered to be important; detailed epigenetic analysis in the medical field has been becoming increasingly important. In the epigenetics analysis, DNA methylation and histone modification analyses have been actively studied for a long time, and many important findings were accumulated. On the other hand, recently, attention has also been focused on RNA modification in the field of epigenetics; now it is known that RNA modification is associated with various biological functions, such as regulation of gene expression. Among RNA modifications, functional analysis of N⁶-methyladenosine (m⁶A), the most abundant RNA modification found from humans to plants is actively progressing, and it has also been known that m⁶A abnormality is involved in cancer and other diseases. Importantly, recent studies have shown that m⁶A is related to viral infections. Considering the current world situation under threat of viral infections, it is important to deepen knowledge of RNA modification from the viewpoint of viral diseases. Hence, in this review, we have summarized the recent findings regarding the roles of RNA modifications in biological functions, cancer biology, and virus infection, particularly focusing on m⁶A in mRNA. Full article

(This article belongs to the Special Issue Epigenetics in Cancer)

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