Educational Activities

Faculty of Pharmaceutical Sciences, The University of Tokyo
Graduate School of Pharmaceutical Sciences, Keio University
Graduate School of Biomedical and Health Sciences, Hiroshima 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 ("aging" 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 "a queen bee" 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.

Figure 1. Telomere as the starting point of cancer biology and drug discovery
Unusual maintenance of chromosome ends, telomeres, supports infinite cancer cell growth. Starting with telomeres, we are focusing on G-quadruplex, poly(ADP-ribose) polymerases and cancer stem cells. Based on these basic researches, we are also developing innovative druggable seeds.

Literature

1. Kawakami, R., Mashima, T., Kawata, N., Kumagai, K., Migita, T., Sano, T., Mizunuma, N., Yamaguchi, K., and Seimiya, H. (2020) ALDH1A3-mTOR axis as a therapeutic target for anticancer drug-tolerant persister cells in gastric cancer. Cancer Sci. 111, 962-973
2. Jang, M. K., Mashima, T., and Seimiya, H. (2020) Tankyrase inhibitors target colorectal cancer stem cells via AXIN-dependent downregulation of c-KIT tyrosine kinase. Mol. Cancer Ther. 19, 765-776
3. Mashima, T., Iwasaki, R., Kawata, N., Kawakami, R., Kumagai, K., Migita, T., Sano, T., Yamaguchi, K., and Seimiya, H. (2019) In silico chemical screening identifies epidermal growth factor receptor as a therapeutic target of drug-tolerant CD44v9-positive gastric cancer cells. Br. J. Cancer 121, 846-856
4. Okamoto, K., Ohishi, T., Kuroiwa, M., Iemura, S. I., Natsume, T., and Seimiya, H. (2018) MERIT40-dependent recruitment of tankyrase to damaged DNA and its implication for cell sensitivity to DNA-damaging anticancer drugs. Oncotarget 9, 35844-35855
5. Mizutani, A., Yashiroda, Y., Muramatsu, Y., Yoshida, H., Chikada, T., Tsumura, T., Okue, M., Shirai, F., Fukami, T., Yoshida, M., and Seimiya, H. (2018) RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model. Cancer Sci. 109, 4003-4014
6. Fujiwara, C., Muramatsu, Y., Nishii, M., Tokunaka, K., Tahara, H., Ueno, M., Yamori, T., Sugimoto, Y., and Seimiya, H. (2018) Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells. Sci. Rep. 8, 14827
7. 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. (2017) APC mutations as a potential biomarker for sensitivity to tankyrase inhibitors in colorectal cancer. Mol. Cancer Ther. 16, 752-762 8. Ohishi, T., Yoshida, H., Katori, M., Migita, T., Muramatsu, Y., Miyake, M., Ishikawa, Y., Saiura, A., Iemura, S. I., Natsume, T., and Seimiya, H. (2017) Tankyrase-binding protein TNKS1BP1 regulates actin cytoskeleton rearrangement and cancer cell invasion. Cancer Res. 77, 2328-2338
9. Nakamura, T., Okabe, S., Yoshida, H., Iida, K., Ma, Y., Sasaki, S., Yamori, T., Shin-Ya, K., Nakano, I., Nagasawa, K., and Seimiya, H. (2017) Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole. Sci. Rep. 7, 3605
10. Mashima, T., Taneda, Y., Jang, M. K., Mizutani, A., Muramatsu, Y., Yoshida, H., Sato, A., Tanaka, N., Sugimoto, Y., and Seimiya, H. (2017) mTOR signaling mediates resistance to tankyrase inhibitors in Wnt-driven colorectal cancer. Oncotarget 8, 47902-47915
11. Ouchi, R., Okabe, S., Migita, T., Nakano, I., and Seimiya, H. (2016) Senescence from glioma stem cell differentiation promotes tumor growth. Biochem. Biophys. Res. Commun. 470, 275-281
12. Hasegawa, D., Okabe, S., Okamoto, K., Nakano, I., Shin-ya, K., and Seimiya, H. (2016) 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
13. Hirashima, K., and Seimiya, H. (2015) 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, 2022-2032
14. Ohishi, T., Muramatsu, Y., Yoshida, H., and Seimiya, H. (2014) TRF1 ensures the centromeric function of Aurora-B and proper chromosome segregation. Mol. Cell. Biol. 34, 2464-2478
15. Migita, T., Okabe, S., Ikeda, K., Igarashi, S., Sugawara, S., Tomida, A., Soga, T., Taguchi, R., and Seimiya, H. (2014) Inhibition of ATP citrate lyase induces triglyceride accumulation with altered fatty acid composition in cancer cells. Int. J. Cancer 135, 37-47
16. Mashima, T., Soma-Nagae, T., Migita, T., Kinoshita, R., Iwamoto, A., Yuasa, T., Yonese, J., Ishikawa, Y., and Seimiya, H. (2014) TRIB1 supports prostate tumorigenesis and tumor-propagating cell survival by regulation of endoplasmic reticulum chaperone expression. Cancer Res. 74, 4888-4897
17. Hirashima, K., Migita, T., Sato, S., Muramatsu, Y., Ishikawa, Y., and Seimiya, H. (2013) Telomere length influences cancer cell differentiation in vivo. Mol. Cell. Biol. 33, 2988-2995
18. 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. (2012) 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, 1268-1280
19. 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. (2012) HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature 489, 313-317
20. 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. (2010) Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 7, 11-14
21. Ohishi, T., Hirota, T., Tsuruo, T., and Seimiya, H. (2010) TRF1 mediates mitotic abnormalities induced by Aurora-A overexpression. Cancer Res. 70, 2041-2052
22. Mashima, T., Sato, S., Sugimoto, Y., Tsuruo, T., and Seimiya, H. (2009) Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions. Oncogene 28, 9-19
23. Seimiya, H., Muramatsu, Y., Ohishi, T., and Tsuruo, T. (2005) Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics. Cancer Cell 7, 25-37
24. Seimiya, H., Muramatsu, Y., Smith, S., and Tsuruo, T. (2004) Functional subdomain in the ankyrin domain of tankyrase 1 required for poly(ADP-ribosyl)ation of TRF1 and telomere elongation. Mol. Cell. Biol. 24, 1944-1955
25. Motiwala, T., Kutay, H., Ghoshal, K., Bai, S., Seimiya, H., Tsuruo, T., Suster, S., Morrison, C., and Jacob, S. T. (2004) Protein tyrosine phosphatase receptor-type O (PTPRO) exhibits characteristics of a candidate tumor suppressor in human lung cancer. Proc. Natl. Acad. Sci. U. S. A. 101, 13844-13849
26. Seimiya, H., and Smith, S. (2002) 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, 14116-14126
27. Seimiya, H., Oh-hara, T., Suzuki, T., Naasani, I., Shimazaki, T., Tsuchiya, K., and Tsuruo, T. (2002) 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, 657-665
28. Seimiya, H., Sawada, H., Muramatsu, Y., Shimizu, M., Ohko, K., Yamane, K., and Tsuruo, T. (2000) Involvement of 14-3-3 proteins in nuclear localization of telomerase. EMBO J. 19, 2652-2661

(Review Articles)
1. Nakanishi, C., and Seimiya, H. (2020) G-quadruplex in cancer biology and drug discovery. Biochem. Biophys. Res. Commun., in press
2. Okamoto, K., and Seimiya, H. (2019) From the wings to the center stage of chromosomes. J. Biol. Chem. 294, 17723-17724
3. Okamoto, K., and Seimiya, H. (2019) Revisiting telomere shortening in cancer. Cells 8, 107

Other Activities

Japanese Cancer Association: Auditor (2020-); Councilor (2006-); Member (2014-) and Chairman (2016-2019) of Conflict of Interest Committee; Member of International Sessions Organizing Committee (2008-2017); Member of International Committee (2015-); Organizing Committee Member of the 11th AACR-JCA Joint Conference (2019); Member of Program Committee of the 66th, 73rd, 75th-80th Annual Meetings
The Japanese Association for Molecular Target Therapy of Cancer: Director (2014-2016); Councilor; Member of Ethics and Conflict of Interest Committee; Member of Program Committee of the 15th, 16th, and 18th-24th Annual Meetings; Member of Executive Committee of the 9th-11th, 13th-16th Translational Research Workshops and the 1st Seeds Needs Workshop
Japanese Society of Medical Oncology: Member of Education Planning Subcommittee (2014-2019); Member of Terminology Subcommittee (2015-2018); Member of Program Committee of the 14th Annual Meeting (2016) Platform of Advanced Animal Model Support (AdAMS), Grant-in-Aid for Scientific Research on Innovative Areas, Ministry of Education, Culture, Sports, Science and Technology, Japan: Group Leader, Molecular Profiling Committee (2016-); Member of Executive Committee of the Technical Training Course for Young Scientists (2016-)
Pharmaceuticals and Medical Devices Agency (PMDA): External Expert (2013-); Member of Working Group for Non-clinical Pharmacology Studies on Anticancer Drugs (2013, 2015-2016)
Science Council of Japan: Member (2017-); Secretary of Subcommittee of Cancer, Committee of Clinical Medicine (2017-)
Japan Society for the Promotion of Science: External Expert (2011 etc.); Commended External Expert (2017) 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) The JFCR International Symposium on Cancer Chemotherapy: Executive Member, Committee Member (2007-); Chairman of Program Committee of the 16th Symposium
Nagoya International Cancer Treatment Symposium: Advisor (2013-)
Japanese Association for RNA Interference: Councilor (2009-); Chairman of Program Committee of the 4th Annual Meeting
Anti-Tumor Drug Development Forum: Councilor, Executive Member (2006-)
Molecular Biology Society of Japan
The Pharmaceutical Society of Japan
American Association for Cancer Research (1996-)
Cancer Science: Secretary for Editor-in-Chief (2002-2008); Associate Editor (2007-)
Journal of Biological Chemistry: Editorial Board Member (2017-)
Frontiers in Cancer Molecular Targets and Therapeutics: Review Editor (2011-)
Journal of Cancer Research and Clinical Oncology: Editorial Board
Gene Expression: Editorial Board

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.

URL

http://www.jfcr.or.jp/english/chemotherapy/department/molecular_biotherapy/