Okayama University Discovery that nitric oxide is a regulatory factor for DNA modification – Succeeded in developing a specific inhibitor and expects its application as a therapeutic agent for diseases such as cancer –

National University Corporation Okayama University
[Okayama University] Discovery that nitric oxide is a regulatory factor for DNA modification – Succeeded in developing a specific inhibitor and expects its application as a therapeutic agent for diseases such as cancer –

February 15, 2023
National University Corporation Okayama University
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-Points of announcement-
DNA methylation modification regulates gene expression, but it is changed by environment and stress, and is involved in the development of various diseases.
It was unclear how this modification was regulated in the body, but we discovered for the first time that nitric oxide (NO) suppresses the activity of DNA methyltransferase.
We have successfully developed an inhibitor and confirmed that it acts extremely effectively against a carcinogenesis model (tumor formation) caused by oxidative stress.
Okayama University (Headquarters: Kita-ku, Okayama City; President: Hiroshi Makino), Faculty of Medicine, Dentistry and Pharmaceutical Sciences (Pharmaceutical Sciences) Professor Takashi Uehara and Scripps Research Institute Professor Stuart A. Lipton, Tokyo Department of Pharmacy Professor Akihiro Ito, Faculty of Life Science, RIKEN, Kam Y.J. Zhang, Team Leader, RIKEN Center for Biosystems Dynamics Research, Professor Futoshi Okada, Faculty of Medicine, Tottori University, Professor Toyomasa Katagiri, Institute for Advanced Enzyme Science, University of Tokushima, Uchida, Graduate School of Agricultural and Life Sciences, University of Tokyo An international joint research group led by Professor Koji has discovered that nitric oxide (NO) induces demethylation of DNA, resulting in the induction of disease-related genes. We have also succeeded in developing a drug that inhibits this phenomenon, demonstrating that NO-induced tumorigenesis is dramatically
On February 4, 2023, the results of this research were published as an article in the British comprehensive science magazine “Nature Communications”.
Higher organisms have a system called epigenetics that regulates gene expression levels through chemical modification of DNA and histones. It is becoming clear that disruption of this mechanism is related to the development of many diseases. NO is known to play an important role in blood pressure regulation, memory formation, sterilization, etc. In this study, it was revealed that NO is an endogenous factor that regulates chemical modification of DNA.
The results of this research showed that NO regulates various gene expressions through regulation of genomic DNA methylation and is also involved in pathogenesis. In the future, it is expected that this will lead not only to health maintenance but also to elucidation of the causes of cancer, central nervous system degenerative diseases, new coronavirus infections, etc.
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Pathogenesis mediated by epigenetic regulation by NO and action of inhibitors A word from Professor Takashi Uehara
At the stage of submitting my paper and conducting additional experiments, the coronavirus pandemic hit, and I had a hard time making progress due to the closure of the laboratory. As a result of these achievements, the number of themes to pursue has increased, and we are currently working on them vigorously.
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Prof. Takashi Uehara
◆ Paper information
 Paper title: Pivotal role for S-nitrosylation of DNA
methyltransferase 3B in epigenetic regulation of tumorigenesis  Publication paper: Nature Communications
Authors: Kosaku Okuda, Kengo Nakahara, Akihiro Ito, Yuta Iijima, Ryosuke Nomura, Ashutosh Kumar, Kana Fujikawa, Kazuya Adachi, Yuki Shimada, Satoshi Fujio, Reina Yamamoto, Nobumasa Takasugi, Kunishige Onuma, Mitsuhiko Osaki, Futoshi Okada, Taichi Ukegawa , Yasuo Takeuchi, Norihisa Yasui, Atsuko Yamashita, Hiroyuki Marusawa, Yosuke Matsushita, Toyomasa Katagiri, Takahiro Shibata, Koji Uchida, Sheng-Yong Niu, Nhi B. Lang, Tomohiro Nakamura, Kam Y. J. Zhang, Stuart A. Lipton & Takashi Uehara
 DO I: 10.1038/s41467-023-36232-6
URL: https://www.nature.com/articles/s41467-023-36232-6
Underlined are graduate and undergraduate students who belong (or were) in our laboratory at Okayama University.
◆ Research funds
This research was supported by the Ministry of Education, Culture, Sports, Science and Technology Grants-in-Aid for Scientific Research (Basic Research B (15H04649) (18H02579), Challenging Exploratory Research (25670029) (15K14952), Scientific Research S (17H06170)), Japan Medical Research and Development Corporation. Agency (AMED) Next-Generation Cancer Medicine Research Project (P-CREATE)
“Development of the latest biomarkers and cancer treatment strategies using the world’s first compound that specifically inhibits the suppression of DNA methyltransferase activity by oxidation
Construction” (19cm0106436h0002), JST Translational Research Strategic Promotion Program (16lm0103011j0003), Research Institute for Advanced Enzyme Science, Tokushima University “Joint Usage/Joint Research” system.
◆About the detailed press release
Discovered that nitric oxide is a regulatory factor for DNA
modification Succeeded in developing a specific inhibitor and expects its application as a therapeutic agent for diseases such as cancer  https://www.okayama-u.ac.jp/up_load_files/press_r4/press20230214-1.pdf ◆ Reference
・Okayama University Faculty of Pharmaceutical Sciences/Graduate School of Medicine, Dentistry and Pharmaceutical Sciences (Pharmaceutical)  https://www.pharm.okayama-u.ac.jp/
・Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
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Okayama University Tsushima Campus (Kita Ward, Okayama City), where Okayama University Faculty of Pharmaceutical Sciences and Graduate School of Biomedical Sciences (Pharmacy)
◆ Inquiries regarding this matter
Takashi Uehara, Professor, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
 Tsushima Campus, Okayama University, 1-1-1 Tsushimanaka, Kita Ward, Okayama City, Okayama Prefecture 700-8530
 TEL & FAX: 086-251-7939
-Inquiries regarding Okayama University’s industry-academia-government collaboration-
 Okayama University Organization for Research Promotion Headquarters for Industry-Academia-Government Collaboration
 1-1-1 Tsushimanaka, Kita-ku, Okayama City, Okayama Prefecture 700-8530  Okayama University Tsushima Campus Main Building 1F  TEL: 086-251-8463
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