Saya, Hideyuki



School of Medicine, Institute for Advanced Medical Research (Division of Gene Regulation) (Shinanomachi)



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  • Hideyuki Saya MD, PhD graduated from Kobe University School of Medicine in 1981 and was Resident in the Neurosurgery until 1983. After which he joined the Graduate School of Medical Sciences granting his PhD in 1987. He studied as a Postdoctoral Fellow in UCSF until 1988 then was appointed Assistant Professor at the Neuro-Oncology, M.D. Anderson Cancer Center. Houston, TX. From 1994 to 2006 he was Professor, Kumamoto University School of Medicine before taking his current position in Keio University School of Medicine in 2007. He is currently a vice president of Keio University Hospital and Director of Clinical and Translational Research Center.

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  • School of Medicine, Professor


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  • The DNA topoisomerase II inhibitor amsacrine as a novel candidate adjuvant in a model of glaucoma filtration surgery

    Yamamoto K., Kokubun T., Sato K., Akaishi T., Shimazaki A., Nakamura M., Shiga Y., Tsuda S., Omodaka K., Saya H., Nakazawa T.

    Scientific Reports (Scientific Reports)  9 ( 1 )  2019.12

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    © 2019, The Author(s). Treatments for refractory glaucoma include trabeculectomy, in which a filtering bleb is created to reduce aqueous pressure. Mitomycin C (MMC) is often used as an adjuvant to reduce post-trabeculectomy bleb scarring and consequent failure. However, scarring sometimes still occurs. Thus, we searched for more effective trabeculectomy adjuvants with high-throughput screening (HTS) of a library of 1,165 off-patent drug compounds. This revealed that amsacrine (AMSA), a DNA topoisomerase II (TOP2) inhibitor, was the top candidate. Compared to MMC, rabbits that underwent trabeculectomy with 10% AMSA had lower IOP at 42, 56, and 70 days (P < 0.01 at all measurement points) and a higher bleb score at 28, 42, 56, and 70 days (P = < 0.01, 0.04, 0.04, and < 0.01, respectively). Compared to saline, rabbits that received 1% AMSA also had lower IOP and better bleb score at all time points, without a sharp drop in IOP just after surgery (all P < 0.01). Both effects were milder than MMC at 7 days (P = 0.02 and <0.01, respectively). Thus, this study showed that HTS may help identify new, promising uses for off-patent drugs. Furthermore, trabeculectomy with AMSA at a suitable concentration may improve the prognosis after trabeculectomy compared to MMC.

  • Ropinirole hydrochloride remedy for amyotrophic lateral sclerosis – Protocol for a randomized, double-blind, placebo-controlled, single-center, and open-label continuation phase I/IIa clinical trial (ROPALS trial)

    Morimoto S., Takahashi S., Fukushima K., Saya H., Suzuki N., Aoki M., Okano H., Nakahara J.

    Regenerative Therapy (Regenerative Therapy)  11   143 - 166 2019.12

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    © 2019 The Japanese Society for Regenerative Medicine Introduction: Amyotrophic lateral sclerosis (ALS) is an intractable and incurable neurological disease. It is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In disease research, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering such results as its preferable transitivity in the brain and tolerability, including possible adverse reactions. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial. Methods: The ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of the ropinirole hydrochloride extended-release tablet (Requip CR) at 2- to 16-mg doses in patients with ALS. Twenty patients will be recruited for the active drug group (fifteen patients) and placebo group (five patients). All patients will be able to receive the standard ALS treatment of riluzole if not changed the dosage during this trial. The primary outcome will be safety and tolerability at 24 weeks, defined from the date of randomization. Secondary outcome will be the efficacy, including any change in the ALS Functional Rating Scale-Revised (ALSFRS-R), change in the Combined Assessment of Function and Survival (CAFS), and the composite endpoint as a sum of Z-transformed scores on various clinical items. Notably, we will perform an explorative search for a drug effect evaluation using the patient-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), an ALSFRS-R score ≥2 points on all items and age from 20 to 80 years. Conclusion: Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020. Trial registration: Current controlled trials UMIN000034954 and JMA-IIA00397 Protocol version: version 1.6 (Date; 5/Apr/2019).

  • Glutaminolysis-related genes determine sensitivity to xCT-targeted therapy in head and neck squamous cell carcinoma

    Okazaki S., Umene K., Yamasaki J., Suina K., Otsuki Y., Yoshikawa M., Minami Y., Masuko T., Kawaguchi S., Nakayama H., Banno K., Aoki D., Saya H., Nagano O.

    Cancer Science (Cancer Science)  110 ( 11 ) 3453 - 3463 2019.11

    ISSN  13479032

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    © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Targeting the function of membrane transporters in cancer stemlike cells is a potential new therapeutic approach. Cystine-glutamate antiporter xCT expressed in CD44 variant (CD44v)-expressing cancer cells contributes to the resistance to oxidative stress as well as cancer therapy through promoting glutathione (GSH)-mediated antioxidant defense. Amino acid transport by xCT might, thus, be a promising target for cancer treatment, whereas the determination factors for cancer cell sensitivity to xCT-targeted therapy remain unclear. Here, we demonstrate that high expression of xCT and glutamine transporter ASCT2 is correlated with undifferentiated status and diminished along with cell differentiation in head and neck squamous cell carcinoma (HNSCC). The cytotoxicity of the xCT inhibitor sulfasalazine relies on ASCT2-dependent glutamine uptake and glutamate dehydrogenase (GLUD)-mediated α-ketoglutarate (α-KG) production. Metabolome analysis revealed that sulfasalazine treatment triggers the increase of glutamate-derived tricarboxylic acid cycle intermediate α-KG, in addition to the decrease of cysteine and GSH content. Furthermore, ablation of GLUD markedly reduced the sulfasalazine cytotoxicity in CD44v-expressing stemlike HNSCC cells. Thus, xCT inhibition by sulfasalazine leads to the impairment of GSH synthesis and enhancement of mitochondrial metabolism, leading to reactive oxygen species (ROS) generation and, thereby, triggers oxidative damage. Our findings establish a rationale for the use of glutamine metabolism (glutaminolysis)-related genes, including ASCT2 and GLUD, as biomarkers to predict the efficacy of xCT-targeted therapy for heterogeneous HNSCC tumors.

  • Neuroprotective effects of memantine via enhancement of autophagy

    Hirano K., Fujimaki M., Sasazawa Y., Yamaguchi A., Ishikawa K., Miyamoto K., Souma S., Furuya N., Imamichi Y., Yamada D., Saya H., Akamatsu W., Saiki S., Hattori N.

    Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  518 ( 1 ) 161 - 170 2019.10

    ISSN  0006291X

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    © 2019 Elsevier Inc. Introduction: Chemical intervention of autophagy has been investigated in clinical trials for various age-related conditions such as sarcopenia and neurodegeneration. However, at present, no autophagy inducer has been established as a disease-modifying agent against neurodegenerative diseases. Methods: We screened a library consisting of 796 medicines clinically approved (in Japan) for autophagy enhancers as potential neurodegeneration therapeutics using HeLa cells stably expressing green fluorescent protein-microtubule-associated protein light chain 3 (GFP-LC3) followed by an analysis of the molecular mechanisms using various neuronal models. Results: The primary screening identified 152 hits in a static cellular state. A widely available Alzheimer's disease drug, memantine, which antagonizes N-Methyl-D-aspartate receptor (NMDAR), was one of the hits. Memantine increased the levels of LC3-II in a dose-dependent and time-dependent manner, and upregulated autophagic flux. In addition, the pharmacological effects of memantine on autophagy were independent of mTORC1 activity and NMDAR activation. Furthermore, a VPS34 inhibitor suppressed the memantine-induced LC3-II upregulation, suggesting that memantine may affect VPS34 complex activity. Notably, intracellular Huntington's disease-specific aggregates of elongated huntingtin, a well-established autophagy substrate, were significantly decreased by memantine. In addition, memantine enhanced elimination of degraded mitochondrial in neurons derived from induced pluripotent stem cells of PARK2 or PARK6 patients, who exhibited defective PINK1/parkin-mediated mitophagy, suggests that memantine accelerated the clearance of damaged mitochondria. Conclusion: These findings indicate that memantine may be beneficial for the treatment of neurodegeneration characterized by the abnormal accumulation of autophagy or mitophagy substrates.

  • IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma

    Kofuji S., Hirayama A., Eberhardt A., Kawaguchi R., Sugiura Y., Sampetrean O., Ikeda Y., Warren M., Sakamoto N., Kitahara S., Yoshino H., Yamashita D., Sumita K., Wolfe K., Lange L., Ikeda S., Shimada H., Minami N., Malhotra A., Morioka S., Ban Y., Asano M., Flanary V., Ramkissoon A., Chow L., Kiyokawa J., Mashimo T., Lucey G., Mareninov S., Ozawa T., Onishi N., Okumura K., Terakawa J., Daikoku T., Wise-Draper T., Majd N., Kofuji K., Sasaki M., Mori M., Kanemura Y., Smith E., Anastasiou D., Wakimoto H., Holland E., Yong W., Horbinski C., Nakano I., DeBerardinis R., Bachoo R., Mischel P., Yasui W., Suematsu M., Saya H., Soga T., Grummt I., Bierhoff H., Sasaki A.

    Nature cell biology (Nature cell biology)  21 ( 8 ) 1003 - 1014 2019.08

    ISSN  14657392

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    In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

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  • 癌細胞シグナル活性化因子14-3-3ζを標的とした新規膵臓癌治療薬の開発


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 佐谷 秀行, Grant-in-Aid for Challenging Research (Exploratory) , Principal Investigator

  • Elucidation of underlyingmechanism of MKL1-mediated induction of cancer associated fibroblasts and its clinical applications


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 佐谷 秀行, Grant-in-Aid for Scientific Research (A) , Principal Investigator


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