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KMID : 0578320220450120886
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Molecules and Cells
2022 Volume.45 No. 12 p.886 ~ p.895
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RUNX1?Survivin Axis Is a Novel Therapeutic Target for Malignant Rhabdoid Tumors
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Mikami Masamitsu
Masuda Tatsuya
Kanatani Takuya
Noura Mina
Umeda Katsutsugu
Hiramatsu Hidefumi
Kubota Hirohito
Daifu Tomoo
Iwai Atsushi
Hattori Etsuko Yamamoto
Furuichi Kana
Takasaki Saho
Tanaka Sunao
Matsui Yasuzumi
Matsuo Hidemasa
Hirata Masahiro
Kataoka Tatsuki R.
Nakahata Tatsutoshi
Kamikubo Yasuhiko
Iehara Tomoko
Hosoi Hajime
Imai Yoichi
Takita Junko
Sugiyama Hiroshi
Adachi Souichi
Kuwahara Yasumichi
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Abstract
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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.
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KEYWORD
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malignant rhabdoid tumor, polyamide, RUNX1, survivin
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