Discovery of Molecular Mechanism Leading to New Treatment Strategy for Malignant Mesothelioma
A research group led by Tokyo University of Technology has discovered a molecular mechanism that could lead to a new treatment strategy for malignant mesothelioma. They found that the DNA repair enzyme USP1 plays a crucial role in the survival of BAP1-mutated cancer cells, suggesting that inhibiting USP1 could selectively induce cancer cell death based on the concept of "synthetic lethality."
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- 📰 Published: May 11, 2026 at 22:35
- 🔍 Collected: May 11, 2026 at 14:01
- 🤖 AI Analyzed: May 11, 2026 at 14:44 (43 min after Collected)
A research group led by Professor Yuko Murakami, Assistant Professor Koya Suzuki, doctoral student Miki Takahashi, and undergraduate student Yuna Kato (at the time of research) of the Department of Applied Biological Science, Tokyo University of Technology (Hachioji City, Tokyo; President: Yutaka Kagawa), in collaboration with 10 research institutions (Note 1) including Aichi Cancer Center Research Institute, National Cancer Center, and Kitasato University School of Medicine, has elucidated a molecular mechanism that could lead to a new treatment strategy for malignant mesothelioma.
This research outcome was published online in the international academic journal "Cell Death & Disease" on May 2, 2026.
【Research Background】
Malignant mesothelioma is one of the difficult-to-treat cancers, with asbestos exposure being the main known cause. Most of its causative genes are tumor suppressor genes, and there is a demand for the development of new therapies based on effective molecular targets. This study focused on "synthetic lethality" (Note 2), a treatment strategy that selectively kills cancer cells while minimizing effects on normal cells by targeting weaknesses dependent on gene mutations specific to cancer cells. For BAP1, one of the causative genes, synthetic lethality specific to cancer cells with this mutation was explored.
【Research Content and Achievements】
The results of this study revealed that USP1, an enzyme involved in DNA repair, plays a crucial role in the survival of BAP1 gene-mutated cells. It was shown that inhibiting USP1 function accumulates DNA damage in BAP1-mutated cells and suppresses cell proliferation. On the other hand, the impact on normal cells was suggested to be relatively limited, indicating its potential as a new therapeutic target. Furthermore, this study clarified that BAP1 and USP1 cooperatively regulate the stability and localization of FANCD2, a protein involved in DNA repair, thereby maintaining DNA repair function. It was suggested that the proliferation of BAP1-mutated cells is supported by the maintenance of DNA repair function via this molecular mechanism (Figure 1).
Figure 1: Model of this research
① In normal mesothelial cells, BAP1 and USP1 cooperate to stabilize FANCD2, and DNA repair is properly performed, allowing cells to survive.
② In mesothelioma cells with BAP1 mutation, FANCD2 is maintained dependently on USP1, and DNA repair is preserved, allowing cells to survive.
③ In cells with normal BAP1, even if USP1 is inhibited, BAP1 functions, so DNA repair is maintained and cells survive.
④ When USP1 is inhibited in BAP1-mutated cells, FANCD2 stability is lost, DNA repair breaks down, and cell death is induced (synthetic lethality).
【Societal and Academic Points】
This research is based on the concept of "synthetic lethality," which selectively induces cell death by utilizing genetic abnormalities specific to cancer cells. It is expected to lead to the development of new therapies for malignant mesothelioma, an intractable cancer. Moving forward, further verification using small molecule compounds and RNA interference technology will be pursued, with the aim of research development towards clinical application.
(Note 1) Aichi Cancer Center Research Institute, National Cancer Center, Kitasato University School of Medicine, Chuo University Faculty of Science and Engineering, Glycoscience Institute (iGCORE), Nagoya University School of Medicine, Juntendo University Faculty of Medical Science, Meijo University Faculty of Pharmacy, Teikyo University School of Medicine, Kinjo Gakuin University Faculty of Pharmacy
(Note 2) Synthetic lethality: A phenomenon where two (or more) genetic abnormalities, each not having a fatal effect on cells individually, lead to cell death when present simultaneously.
【Paper Information】
Paper title: BAP1 and USP1 Cooperate to Regulate FANCD2 Stability and Cell Proliferation in Mesothelioma Cells
Authors: Koya Suzuki, Shinichi Kiyonari, Jo Nishino, Miki Takahashi, Yuna Kato, Miki Amano, Anna Ogiso, Tomohiro Akashi, Tohru Maeda, Norio Kaneda, Takashi Miida, Yutaka Kondo, Kenji Kadomatsu, Mamoru Kato, Koji Aoyama, Hiroshi Murakami, Yoshitaka Sekido and Yuko Murakami-Tonami
Journal name: Cell Death & Disease
Publication date: May 2, 2026
DOI: 10.1038/s41419-026-08818-7
URL: https://www.nature.com/articles/s41419-026-08818-7
■Tokyo University of Technology, Department of Applied Biological Science, Tumor Molecular Genetics (Yuko Murakami) Laboratory
Gene abnormalities and cell in cancer
Keywords:
This research outcome was published online in the international academic journal "Cell Death & Disease" on May 2, 2026.
【Research Background】
Malignant mesothelioma is one of the difficult-to-treat cancers, with asbestos exposure being the main known cause. Most of its causative genes are tumor suppressor genes, and there is a demand for the development of new therapies based on effective molecular targets. This study focused on "synthetic lethality" (Note 2), a treatment strategy that selectively kills cancer cells while minimizing effects on normal cells by targeting weaknesses dependent on gene mutations specific to cancer cells. For BAP1, one of the causative genes, synthetic lethality specific to cancer cells with this mutation was explored.
【Research Content and Achievements】
The results of this study revealed that USP1, an enzyme involved in DNA repair, plays a crucial role in the survival of BAP1 gene-mutated cells. It was shown that inhibiting USP1 function accumulates DNA damage in BAP1-mutated cells and suppresses cell proliferation. On the other hand, the impact on normal cells was suggested to be relatively limited, indicating its potential as a new therapeutic target. Furthermore, this study clarified that BAP1 and USP1 cooperatively regulate the stability and localization of FANCD2, a protein involved in DNA repair, thereby maintaining DNA repair function. It was suggested that the proliferation of BAP1-mutated cells is supported by the maintenance of DNA repair function via this molecular mechanism (Figure 1).
Figure 1: Model of this research
① In normal mesothelial cells, BAP1 and USP1 cooperate to stabilize FANCD2, and DNA repair is properly performed, allowing cells to survive.
② In mesothelioma cells with BAP1 mutation, FANCD2 is maintained dependently on USP1, and DNA repair is preserved, allowing cells to survive.
③ In cells with normal BAP1, even if USP1 is inhibited, BAP1 functions, so DNA repair is maintained and cells survive.
④ When USP1 is inhibited in BAP1-mutated cells, FANCD2 stability is lost, DNA repair breaks down, and cell death is induced (synthetic lethality).
【Societal and Academic Points】
This research is based on the concept of "synthetic lethality," which selectively induces cell death by utilizing genetic abnormalities specific to cancer cells. It is expected to lead to the development of new therapies for malignant mesothelioma, an intractable cancer. Moving forward, further verification using small molecule compounds and RNA interference technology will be pursued, with the aim of research development towards clinical application.
(Note 1) Aichi Cancer Center Research Institute, National Cancer Center, Kitasato University School of Medicine, Chuo University Faculty of Science and Engineering, Glycoscience Institute (iGCORE), Nagoya University School of Medicine, Juntendo University Faculty of Medical Science, Meijo University Faculty of Pharmacy, Teikyo University School of Medicine, Kinjo Gakuin University Faculty of Pharmacy
(Note 2) Synthetic lethality: A phenomenon where two (or more) genetic abnormalities, each not having a fatal effect on cells individually, lead to cell death when present simultaneously.
【Paper Information】
Paper title: BAP1 and USP1 Cooperate to Regulate FANCD2 Stability and Cell Proliferation in Mesothelioma Cells
Authors: Koya Suzuki, Shinichi Kiyonari, Jo Nishino, Miki Takahashi, Yuna Kato, Miki Amano, Anna Ogiso, Tomohiro Akashi, Tohru Maeda, Norio Kaneda, Takashi Miida, Yutaka Kondo, Kenji Kadomatsu, Mamoru Kato, Koji Aoyama, Hiroshi Murakami, Yoshitaka Sekido and Yuko Murakami-Tonami
Journal name: Cell Death & Disease
Publication date: May 2, 2026
DOI: 10.1038/s41419-026-08818-7
URL: https://www.nature.com/articles/s41419-026-08818-7
■Tokyo University of Technology, Department of Applied Biological Science, Tumor Molecular Genetics (Yuko Murakami) Laboratory
Gene abnormalities and cell in cancer
Keywords: