Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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RUNX1-Survivin Axis Is a Novel Therapeutic Target for Malignant Rhabdoid Tumors

  • Masamitsu, Mikami (Department of Pediatrics, Graduate School of Medicine, Kyoto University) ;
  • Tatsuya, Masuda (Department of Human Health Sciences, Graduate School of Medicine, Kyoto University) ;
  • Takuya, Kanatani (Department of Human Health Sciences, Graduate School of Medicine, Kyoto University) ;
  • Mina, Noura (Department of Human Health Sciences, Graduate School of Medicine, Kyoto University) ;
  • Katsutsugu, Umeda (Department of Pediatrics, Graduate School of Medicine, Kyoto University) ;
  • Hidefumi, Hiramatsu (Department of Pediatrics, Graduate School of Medicine, Kyoto University) ;
  • Hirohito, Kubota (Department of Pediatrics, Graduate School of Medicine, Kyoto University) ;
  • Tomoo, Daifu (Department of Pediatrics, Graduate School of Medicine, Kyoto University) ;
  • Atsushi, Iwai (Department of Pediatrics, Graduate School of Medicine, Kyoto University) ;
  • Etsuko Yamamoto, Hattori (Department of Human Health Sciences, Graduate School of Medicine, Kyoto University) ;
  • Kana, Furuichi (Department of Human Health Sciences, Graduate School of Medicine, Kyoto University) ;
  • Saho, Takasaki (Department of Human Health Sciences, Graduate School of Medicine, Kyoto University) ;
  • Sunao, Tanaka (Department of Human Health Sciences, Graduate School of Medicine, Kyoto University) ;
  • Yasuzumi, Matsui (Department of Human Health Sciences, Graduate School of Medicine, Kyoto University) ;
  • Hidemasa, Matsuo (Department of Human Health Sciences, Graduate School of Medicine, Kyoto University) ;
  • Masahiro, Hirata (Department of Diagnostic Pathology, Kyoto University Hospital) ;
  • Tatsuki R., Kataoka (Department of Diagnostic Pathology, Kyoto University Hospital) ;
  • Tatsutoshi, Nakahata (Drug Discovery Technology Development Office, Center for iPS Cell Research and Application (CiRA), Kyoto University) ;
  • Yasumichi, Kuwahara (Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine) ;
  • Tomoko, Iehara (Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine) ;
  • Hajime, Hosoi (Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine) ;
  • Yoichi, Imai (Department of Hematology/Oncology, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo) ;
  • Junko, Takita (Department of Pediatrics, Graduate School of Medicine, Kyoto University) ;
  • Hiroshi, Sugiyama (Department of Chemistry, Graduate School of Science, Kyoto University) ;
  • Souichi, Adachi (Department of Human Health Sciences, Graduate School of Medicine, Kyoto University) ;
  • Yasuhiko, Kamikubo (Department of Human Health Sciences, Graduate School of Medicine, Kyoto University)
  • Received : 2021.11.23
  • Accepted : 2022.08.06
  • Published : 2022.12.31
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Abstract

Malignant rhabdoid tumor (MRT) is a highly aggressive pediatric malignancy with no effective therapy. Therefore, it is necessary to identify a target for the development of novel molecule-targeting therapeutic agents. In this study, we report the importance of the runt-related transcription factor 1 (RUNX1) and RUNX1-Baculoviral IAP (inhibitor of apoptosis) Repeat-Containing 5 (BIRC5/survivin) axis in the proliferation of MRT cells, as it can be used as an ideal target for anti-tumor strategies. The mechanism of this reaction can be explained by the interaction of RUNX1 with the RUNX1-binding DNA sequence located in the survivin promoter and its positive regulation. Specific knockdown of RUNX1 led to decreased expression of survivin, which subsequently suppressed the proliferation of MRT cells in vitro and in vivo. We also found that our novel RUNX inhibitor, Chb-M, which switches off RUNX1 using alkylating agent-conjugated pyrrole-imidazole polyamides designed to specifically bind to consensus RUNX-binding sequences (5'-TGTGGT-3'), inhibited survivin expression in vivo. Taken together, we identified a novel interaction between RUNX1 and survivin in MRT. Therefore the negative regulation of RUNX1 activity may be a novel strategy for MRT treatment.

Keywords

Acknowledgement

This research was supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]; 19am0101101j0003), Basic Science and Platform Technology Program for Innovative Biological Medicine from the Japan Agency for Medical Research and Development (AMED; 15am0301005h0002), Grant from the International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo, and a Grant-in-Aid for Scientific Research from KAKENHI (17H03597). We would like to thank Dr. H. Miyoshi (RIKEN BRC) for kindly providing the lentiviral vector encoding CSIV-TRE-RfA-UbC-KT for this study.

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