Embargoed until 0:00 JST, 28 JUL 2020
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News Release
July 28, 2020
Chiba University

Epstein-Barr virus rewires host epigenomes
to drive stomach cancer––Researchers in Japan and Singapore have discovered a molecular mechanism that explains
how Epstein-Barr virus (EBV) infection alters a host’s epigenome to promote tumorigenesis(the transformation of normal cells into cancer cells) in certain types of stomach cancer.
The findings suggest that EBV infection plays an important role in the development of EBVassociated stomach cancers, and provide fresh insights that may lead to new therapies forstomach and other virus-related malignancies.

Chiba, 28 July 2020 – The Epstein-Barr virus (EBV), one of the most common human viruses, isassociated with about 8–10 per cent of stomach — or gastric — cancers, the third leading causeof cancer death globally. Researchers from Chiba University in Japan, Duke-NUS Medical
School, Singapore, and the Agency for Science, Technology and Research (A*STAR)’s Genome
Institute of Singapore (GIS) have revealed a novel paradigm in EBV-associated gastric cancer,
whereby the EBV viral genome directly alters the host epigenetic landscape to promote theactivation of proto-oncogenes (genes involved in normal cell growth that can mutate into cancercausing genes) and tumorigenesis.
The human genome is the complete set of human genetic information, and the epigenome
describes modifications to the genome that determine whether genes are turned on or off when
and where they are needed. Unlike genetic information, the epigenome is dynamic andresponsive to external stimuli; certain external stimuli can cause abnormal DNA modifications
which, in turn, can disrupt normal gene expression and contribute to cancer development.
The research group, led by senior and co-corresponding authors, Dr Atsushi Kaneda, Professor
at the Graduate School of Medicine, Chiba University, and Dr Patrick Tan, Professor at theProgramme in Cancer and Stem Cell Biology, Duke-NUS Medical School, and Executive Directorof GIS, conducted a comprehensive analysis of three-dimensional genomic structures in humancells. These ranged from gastric cancer cell lines, patient samples, normal gastric epithelial cells,and EBV-associated gastric cancer. Combined with virus infection analyses, the researchers
found abnormally activated genomic regions specific to EBV-positive stomach cancer.
Experimental EBV infection of cultured stomach cells reproduced the phenomena of EBV binding
to these inactive and closed genomic regions and their abnormal activation.
‟Cells put active marks on genomic regions necessary for their behaviours and utilise them, andinactive marks on unnecessary genomic regions that are tightly closed and not to be utilised,”
explained Prof Kaneda. “We made the striking observation that strong inactive marks were lost in
specific genomic regions when we infected stomach cells with EBV.”The researchers further found that genetic enhancers (short pieces of DNA that help encourage
genes to make proteins) ‘silenced’ in the closed regions were activated by the virus to upregulate
nearby cancer-related genes, leading to the proliferation of cancerous cells. This ‘enhancer
infestation’ model, as the researchers termed it, reveals a novel mechanism of tumorigenesis

Page 1 of 5that does not require genetic alterations, and instead works by reprograming the epigenetic
landscape of human cells to convert latent enhancers from a silenced to an active state.
Prof Patrick Tan, who is also a member of the Singapore Gastric Cancer Consortium, remarked,‟In all EBV-positive stomach cancer cells and primary stomach cancer patient samples studied,
EBV DNA bound to largely the same genomic regions that also showed abnormal activation.
These same regions also changed from inactive to active states by experimental EBV infection.”
This mechanism of ‘enhancer infestation’ led to the activation of neighbouring proto-oncogenes
in human cells and it is likely to contribute to EBV-associated oncogenesis in multiple cancer celltypes. Notably, the researchers also found that, even after eliminating EBV genomes, epigenetic
modifications that were induced continued to persist, suggesting a ‘hit-and-run’ mechanism, inwhich once an EBV episome alters the chromatin topology of human cells, these alteredtopologies are then stable and persist even after removal of the EBV episome.
Prof Kaneda reiterated, “While 8–10 per cent of stomach cancer is associated with EBV, webelieve our enhancer infestation model provides a new mechanism of cancer involving
epigenomic alterations and viral infection that may be relevant to a broader range of cancers andassociated diseases.”
Prof Tan added, “Infections by EBV are estimated to cause over 200,000 cancers per year
worldwide, including certain stomach cancers. Our study highlights new potential drug targets in
EBV-positive malignancies, revealed by epigenetics and previously invisible using moreconventional genetic sequencing studies.”###Reference: Okabe, A., Huang, K.K., Matsusaka, K. et al. Cross species chromatin interactions drive
transcriptional rewiring in Epstein Barr virus positive gastric adenocarcinoma. Nature Genetics (2020).
https://doi.org./10.1038/s41588-020-0665-7 (Direct link to the paper)

About Chiba University Graduate School of Medicine
Chiba University was founded in 1949, unifying several regional former national colleges andschools. Since then, pursuing the goals of excellence has resulted in Chiba University becoming
one of the leading academic research centres of Japan.
The history of Chiba University Graduate School of Medicine can be traced back as early as
1874, when its predecessor was founded. Chiba University Graduate School of Medicine focus
on the promotion of research in "Innovative Therapeutics", a new field that connects basic andclinical medicine.
Chiba University offers “Innovative Medicine CHIBA Doctoral WISE Program (iMeC-WISE)”
supported by Japanese government. Based on the 100-year history in the fields of medicine andpharmaceutical sciences, iMeC-WISE aims to foster the next generation of world-classresearchers and innovators, who will contribute to the development of medical sciences, pave
the way to novel therapies and drugs, and develop sustainable healthcare systems.
For more information about Chiba University, please visit http://www.chiba-u.ac.jp/e/index.html

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About Duke-NUS Medical School
Duke-NUS is Singapore’s flagship graduate entry medical school, established in 2005 with astrategic, government-led partnership between two world-class institutions: Duke University
School of Medicine and the National University of Singapore (NUS). Through an innovative
curriculum, students at Duke-NUS are nurtured to become multi-faceted ‘Clinicians Plus’ poised
to steer the healthcare and biomedical ecosystem in Singapore and beyond. A leader in groundbreaking research and translational innovation, Duke-NUS has gained international renown
through its five signature research programmes and nine centres. The enduring impact of its
discoveries is amplified by its successful Academic Medicine partnership with Singapore HealthServices (SingHealth), Singapore’s largest healthcare group. This strategic alliance has spawned
15 Academic Clinical Programmes, which harness multi-disciplinary research and education totransform medicine and improve lives.
For more information, please visit www.duke-nus.edu.sg

About A*STAR’s Genome Institute of Singapore (GIS)The Genome Institute of Singapore (GIS) is an institute of the Agency for Science, Technologyand Research (A*STAR). It has a global vision that seeks to use genomic sciences to achieve
extraordinary improvements in human health and public prosperity. Established in 2000 as acentre for genomic discovery, the GIS pursues the integration of technology, genetics and biology
towards academic, economic and societal impact, with a mission to “read, reveal and write DNA
for a better Singapore and world”.
Key research areas at the GIS include Precision Medicine & Population Genomics, Genome
Informatics, Spatial & Single Cell Systems, Epigenetic & Epitranscriptomic Regulation, Genome
Architecture & Design, and Sequencing Platforms. The genomics infrastructure at the GIS is alsoutilised to train new scientific talent, to function as a bridge for academic and industrial research,and to explore scientific questions of high impact.
For more information about GIS, please visit www.a-star.edu.sg/gis.

About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector
R&D agency, spearheading economic-oriented research to advance scientific discovery anddevelop innovative technology. Through open innovation, we collaborate with our partners in boththe public and private sectors to benefit society.
As a Science and Technology Organisation, A*STAR bridges the gap between academia andindustry. Our research creates economic growth and jobs for Singapore, and enhances lives bycontributing to societal benefits such as improving outcomes in healthcare, urban living, andsustainability.
We play a key role in nurturing and developing a diversity of talent and leaders in our Agency andresearch entities, the wider research community and industry. A*STAR’s R&D activities spanbiomedical sciences and physical sciences and engineering, with research entities primarily
located in Biopolis and Fusionopolis. For ongoing news, visit www.a-star.edu.sg.
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For media enquiries, please contact:
Hiroshi Sodeyama
Vice Head Administrator, General Affairs Division
Inohana Campus Administration
Chiba University
Tel: +81-43-226-2946
Email: inohana-koho@chiba-u.jp
Federico Graciano
Senior Media & Content Specialist
Communications & Strategic Relations
Duke-NUS Medical School
Tel: +65 6601 3272
Email: f.graciano@duke-nus.edu.sg
Lyn Lai
Officer, Office of Corporate Communications
Genome Institute of Singapore, A*STAR
Tel: +65 6808 8258 | HP: +65 8755 8759
Email: laiy@gis.a-star.edu.sg

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Suggested image

Caption: Schematic model of Epstein-Barr virus (EBV) enhancer infestation driving
heterochromatin, epigenomic and transcriptional rewiring in EBV-positive gastric cancers.
(i) Enhancers silenced in the closed heterochromatin region (pale blue box).
(ii) EBV DNA bound to the closed regions (blue circle).
(iii) Rewiring from inactive to active state where the closed regions are opened, the silenced
enhancers are activated, and the neighbouring proto-oncogenes are activated.
Credit: Chiba University | Duke-NUS Medical School | Genome Institute of Singapore

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