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Hiroyuki Seimiya / Associate Professor / Division of Biosciences
Department of Computational Biology and Medical Sciences / / Molecular cancer therapeutics, telomere biology, G-quadruplex, poly(ADP-ribosyl)ation, cancer stem cells
http://www.jfcr.or.jp/english/chemotherapy/department/molecular_biotherapy/

Career Summary
1990: B.Sc., Faculty of Pharmaceutical Sciences, The University of Tokyo
1995: Ph.D. (Doctor of Pharmaceutical Sciences), The University of Tokyo
1993-1995: Predoctoral Fellow in Cancer Research, Japan Society for the Promotion of Science
1995-2004: Research Associate, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
2000-2001: Postdoctoral Fellow, New York University School of Medicine
2004: Associate Member, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
2005-Present: Member and Chief (Principal Investigator), Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
2008-Present: Visiting Professor, Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University (concurrent)
2009-Present: Visiting Professor, Institute of Health Biosciences, The University of Tokushima Graduate School (concurrent)
2010-Present: Visiting Associate Professor, Graduate School of Frontier Sciences, The University of Tokyo (concurrent)
2014-Present: Visiting Professor, Graduate School of Medicine, Yokohama City University (concurrent)
2017-Present: Visiting Professor, Graduate School of Biomedical & Health Sciences, Hiroshima University (concurrent)

Educational Activities
Faculty of Pharmaceutical Sciences, The University of Tokyo
Graduate School of Pharmaceutical Sciences, Keio University

Research Activities
1. Telomere dynamics and cancer
To proliferate, cells need to replicate their DNA. However, classical replication machinery cannot completely replicate the very ends of chromosomes (telomeres). Therefore, telomeres, which are specialized structures that protect eukaryotic chromosome termini, gradually shorten after each cell cycle. When telomeres reach the limit of shortening, the cells cannot divide any further. This phenomenon, called replicative senescence (gagingh of a cell), is one of the systems that prevent carcinogenesis. In most cancer cells, the telomere-synthesizing enzyme, telomerase, stably maintains telomeres. Accordingly, cancer cells have the ability to divide infinitely. We have developed a series of telomerase inhibitors that block the unlimited growth of cancer cells. Now we are pursuing basic research on the telomeric non-coding RNA (TERRA)-mediated regulation of cancer progression and the development research of new anticancer drugs that target G-quadruplex, a specialized higher-order structure of telomeric and other G-rich nucleic acids.


2. Cell regulation by poly(ADP-ribosyl)ation
Poly(ADP-ribosyl)ation (PARsylation), one of the most dramatic post-translational modifications of proteins, is catalyzed by poly(ADP-ribose) polymerases (PARP). PARsylation regulates various biological events, including genomic stability, gene transcription, and so forth. We still have many questions about this process, such as the molecular basis for functional specificity elicited from PAR chains. Recently, PARP1/2 inhibitors have been approved as synthetic lethal therapeutic drugs against BRCA1/2-deficient cancer cells, and other PARP family enzymes have also been postulated as therapeutic targets. We focus on tankyrases, the PARP members that enhance telomere elongation by telomerase and promote the oncogenic Wnt/beta-catenin signaling in human cancer cells. We are developing tankyrase inhibitors as innovative anticancer drugs and pursuing research on biomarkers that predict the efficacy of tankyrase inhibitors.


3. Cancer stem cells as therapeutic targets
Cancer heterogeneity is derived from stochastic clonal evolution and cellular hierarchy, in the latter of which cancer stem cells (CSCs) reside on the top position. CSCs, which are self-renewable, multipotent, and highly tumorigenic, exhibit drug resistance and a metastatic potential. Therefore, CSCs are postulated as ga queen beeh that hinders cancer eradication. Molecular signaling pathways and microenvironmental niches that regulate survival, proliferation, and stemness of CSCs have been identified from various cancers. These factors would be promising targets for anticancer drug development. In our laboratory, we focus on glioma stem cells and gastric CSCs. Specifically, we utilize functional genomics and comprehensive transcriptome analyses to pursue therapeutic targets of CSCs. We are also developing chemical compounds called G-quadruplex ligands, which have a preferential anti-proliferative effect on glioma stem cells.


Literature
1. Ohishi T., Yoshida H., Katori M., Migita T., Muramatsu Y., Miyake M., Ishikawa Y., Saiura A., Iemura S.I., Natsume T., and Seimiya H. Tankyrase-binding protein TNKS1BP1 regulates actin cytoskeleton rearrangement and cancer cell invasion. Cancer Res, 77: 2328-2338 (2017).
2. Tanaka N., Mashima T., Mizutani A., Sato A., Aoyama A., Gong B., Yoshida H., Muramatsu Y., Nakata K., Matsuura M., Katayama R., Nagayama S., Fujita N., Sugimoto Y., and Seimiya H. APC mutations as a potential biomarker for sensitivity to tankyrase inhibitors in colorectal cancer. Mol Cancer Ther, 16: 752-62 (2017).
3. Ouchi R., Okabe S., Migita T., Nakano I., and Seimiya H. Senescence from glioma stem cell differentiation promotes tumor growth. Biochem Biophys Res Commun, 470: 275-81 (2016).
4. Hasegawa D., Okabe S., Okamoto K., Nakano I., Shin-ya K., and Seimiya H. G-quadruplex ligand-induced DNA damage response coupled with telomere dysfunction and replication stress in glioma stem cells. Biochem Biophys Res Commun, 471: 75-81 (2016).
5. Seimiya H. Predicting Risk at the End of the End: Telomere G-tail as a Biomarker. EBioMedicine, 2: 804-5 (2015).
6. Hirashima K. and Seimiya H. Telomeric repeat-containing RNA/G-quadruplex-forming sequences cause genome-wide alteration of gene expression in human cancer cells in vivo. Nucleic Acids Res, 43: 2022-32 (2015).
7. Ohishi T., Muramatsu Y., Yoshida H., and Seimiya H. TRF1 ensures the centromeric function of Aurora-B and proper chromosome segregation. Mol Cell Biol, 34: 2464-78 (2014).
8. Mashima T., Soma-Nagae T., Migita T., Kinoshita R., Iwamoto A., Yuasa T., Yonese J., Ishikawa Y., and Seimiya H. TRIB1 supports prostate tumorigenesis and tumor-propagating cell survival by regulation of endoplasmic reticulum chaperone expression. Cancer Res, 74: 4888-97 (2014).
9. Migita T., Okabe S., Ikeda K., Igarashi S., Sugawara S., Tomida A., Soga T., Taguchi R., and Seimiya H. Inhibition of ATP citrate lyase induces triglyceride accumulation with altered fatty acid composition in cancer cells. Int J Cancer, 135: 37-47 (2014).
10. Hirashima K., Migita T., Sato S., Muramatsu Y., Ishikawa Y., and Seimiya H. Telomere length influences cancer cell differentiation in vivo. Mol Cell Biol, 33: 2988-95 (2013).
11. Miyazaki T., Pan Y., Joshi K., Purohit D., Hu B., Demir H., Mazumder S., Okabe S., Yamori T., Viapiano M., Shin-ya K., Seimiya H., and Nakano I. Telomestatin impairs glioma stem cell survival and growth through the disruption of telomeric G-quadruplex and inhibition of the proto-oncogene, c-Myb. Clin Cancer Res, 18: 1268-80 (2012).
12. Deardorff M.A., Bando M., Nakato R., Watrin E., Itoh T., Minamino M., Saitoh K., Komata M., Katou Y., Clark D., Cole K.E., De Baere E., Decroos C., Di Donato N., Ernst S., Francey L.J., Gyftodimou Y., Hirashima K., Hullings M., Ishikawa Y., Jaulin C., Kaur M., Kiyono T., Lombardi P.M., Magnaghi-Jaulin L., Mortier G.R., Nozaki N., Petersen M.B., Seimiya H., Siu V.M., Suzuki Y., Takagaki K., Wilde J.J., Willems P.J., Prigent C., Gillessen-Kaesbach G., Christianson D.W., Kaiser F.J., Jackson L.G., Hirota T., Krantz I.D., and Shirahige K. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature, 489: 313-7 (2012).
13. Seki T., Yuasa S., Oda M., Egashira T., Yae K., Kusumoto D., Nakata H., Tohyama S., Hashimoto H., Kodaira M., Okada Y., Seimiya H., Fusaki N., Hasegawa M., and Fukuda K. Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell, 7: 11-4 (2010).
14. Ohishi T., Hirota T., Tsuruo T., and Seimiya H. TRF1 mediates mitotic abnormalities induced by Aurora-A overexpression. Cancer Res, 70: 2041-52 (2010).
15. Mashima T., Sato S., Sugimoto Y., Tsuruo T., and Seimiya H. Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions. Oncogene, 28: 9-19 (2009).
16. Seimiya H., Muramatsu Y., Ohishi T., and Tsuruo T. Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics. Cancer Cell, 7: 25-37 (2005).
17. Seimiya H., Muramatsu Y., Smith S., and Tsuruo T. Functional subdomain in the ankyrin domain of tankyrase 1 required for poly(ADP-ribosyl)ation of TRF1 and telomere elongation. Mol Cell Biol, 24: 1944-55 (2004).
18. Seimiya H. and Smith S. The telomeric poly(ADP-ribose) polymerase, tankyrase 1, contains multiple binding sites for telomeric repeat binding factor 1 (TRF1) and a novel acceptor, 182-kDa tankyrase-binding protein (TAB182). J Biol Chem, 277: 14116-26 (2002).
19. Seimiya H., Oh-hara T., Suzuki T., Naasani I., Shimazaki T., Tsuchiya K., and Tsuruo T. Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-199. Mol Cancer Ther, 1: 657-65 (2002).
20. Seimiya H., Sawada H., Muramatsu Y., Shimizu M., Ohko K., Yamane K., and Tsuruo T. Involvement of 14-3-3 proteins in nuclear localization of telomerase. EMBO J, 19: 2652-61 (2000).

Other Activities
Japanese Cancer Association (Councilor, Chairman of Conflict of Interest Committee, Member of International Sessions Organizing Committee, Member of International Committee, Member of Program Committee of the 66th, 73rd, 75th, and 76th Annual Meetings)
The Japanese Association for Molecular Target Therapy of Cancer (Councilor, Director, Member of Ethics and Conflict of Interest Committee, Member of Program Committee of the 15th, 16th, and 18th-21st Annual Meetings, Member of Executive Committee of the 9th-11th Translational Research Workshops)
Japanese Society of Medical Oncology (Member of Education Planning Subcommittee, Member of Terminology Subcommittee, Member of Program Committee of the 14th Annual Meeting)
Pharmaceuticals and Medical Devices Agency (External Expert, Member of Working Group for Non-clinical Pharmacology Studies on Anticancer Drugs)
The JFCR International Symposium on Cancer Chemotherapy (Executive Member, Chairman of Program Committee of the 16th Symposium)
Japanese Association for RNA Interference (Councilor, Chairman of Program Committee of the 4th Annual Meeting)
Anti-Tumor Drug Development Forum (Councilor, Executive Member)
Molecular Biology Society of Japan
The Pharmaceutical Society of Japan
American Association for Cancer Research
Scientific Support Programs for Cancer Research, Grant-in-Aid for Scientific Research on Innovative Areas, Ministry of Education, Culture, Sports, Science and Technology, Japan [Member (2005-2014), Group Leader (2015), Screening Committee of Anticancer Drugs; Executive Member of Young Scientist Workshop (2011-2015)]
Platform of Advanced Animal Model Support, Grant-in-Aid for Scientific Research on Innovative Areas, Ministry of Education, Culture, Sports, Science and Technology, Japan [Group Leader, Molecular Profiling Committee]
Cancer Science [Secretary for Editor-in-Chief (2002-2008), Associate Editor]
Frontiers in Cancer Molecular Targets and Therapeutics (Review Editor)
Journal of Cancer Research and Clinical Oncology (Editorial Board)
Gene Expression (Editorial Board)
Journal of Biological Chemistry (Editorial Board Member)

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Future Plan
Our goals are to pinpoint the Achilles' heels of cancers at the molecular level and to develop anticancer therapeutics directed against such molecular targets. We especially focus on (i) telomeres, which are associated with cellular replicative capacity, (ii) poly(ADP-ribose) polymerases, which are involved in genomic stability, and (iii) cancer stem cells, which contribute to the propagation and relapse of cancers. We would like to elucidate the molecular bases of system failures in those events and cure cancers by correcting or blocking them.

Messages to Students
Gradually aging cells as observed through the lens of a microscope will remind you that you only live once. Asking yourself how you can enrich your limited life will make your thoughts and actions proactive, which is not only essential for conducting research but will also, I believe, motivate your colleagues. Good luck with your life and research.
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