Tokyo University of Technology Research Group Identifies a Novel Therapeutic Strategy for Mesothelioma

A research group led by Professor Yuko Murakami-Tonami of the School of Bioscience and Biotechnology, Tokyo University of Technology, together with Laboratory Instructor Koya Suzuki, Master's student Miki Takahashi, and undergraduate student (at the time of the study) Yuna Kato, has uncovered a molecular mechanism that may lead to a new therapeutic strategy for malignant mesothelioma. The study was conducted in collaboration with researchers from ten institutions, including the Aichi Cancer Center Research Institute, National Cancer Center Japan Research Institute, and Kitasato University School of Medicine (Note 1).
The findings were published online in the international journal Cell Death & Disease on May 2, 2026.

Background
Mesothelioma is one of the most difficult cancers to treat and is primarily caused by exposure to asbestos. Since most of its driver genes are tumor suppressor genes, the development of novel molecularly targeted therapies remains a major challenge.
In this study, the researchers focused on synthetic lethality (Note 2), a therapeutic strategy that selectively kills cancer cells by targeting vulnerabilities created by cancer-specific genetic alterations while minimizing damage to normal cells. They investigated synthetic lethal interactions involving BAP1, one of the major driver genes frequently mutated in malignant mesothelioma.

Research Findings
The study identified the DNA repair enzyme USP1 as an essential factor for the survival of BAP1-deficient mesothelioma cells. Inhibition of USP1 resulted in the accumulation of DNA damage and suppression of cell proliferation specifically in BAP1-deficient cells, while the effects on normal cells appeared to be relatively limited, suggesting that USP1 represents a promising therapeutic target.
Furthermore, the researchers demonstrated that BAP1 and USP1 cooperatively regulate the stability and localization of FANCD2, a key protein involved in DNA repair. This cooperative mechanism maintains DNA repair capacity and supports the survival and proliferation of BAP1-mutant mesothelioma cells (Figure 1).

Specifically:
1.In normal mesothelial cells, BAP1 and USP1 cooperate to stabilize FANCD2, allowing efficient DNA repair and cell survival.
2.In BAP1-deficient mesothelioma cells, FANCD2 is maintained through USP1-dependent mechanisms, preserving DNA repair activity and enabling cell survival.
3.In cells with functional BAP1, inhibition of USP1 alone does not abolish DNA repair because BAP1 compensates for the loss of USP1 activity.
4.In contrast, inhibition of USP1 in BAP1-deficient cells destabilizes FANCD2, disrupts DNA repair, and induces cell death through synthetic lethality.

Significance
This study demonstrates a novel synthetic lethal interaction that selectively targets cancer cells carrying BAP1 deficiency, providing a promising strategy for the treatment of malignant mesothelioma.
The researchers plan to further validate this therapeutic approach using small-molecule compounds and RNA interference technologies, with the ultimate goal of translating these findings into clinical applications.

Note 1
Collaborating institutions: Aichi Cancer Center Research Institute, National Cancer Center Japan Research Institute, Kitasato University School of Medicine, Faculty of Science and Engineering, Chuo University, Institute for Glyco-core Research (iGCORE), Nagoya University Graduate School of Medicine, Juntendo University Faculty of Health Science, Meijo University Faculty of Pharmacy, Teikyo University School of Medicine, and Kinjo Gakuin University Faculty of Pharmacy.

Note 2
Synthetic lethality refers to a phenomenon in which simultaneous impairment of two (or more) genes, each of which alone is not lethal, results in cell death.
Publication Information
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: Cell Death & Disease
Published online: May 2, 2026
DOI: 10.1038/s41419-026-08818-7
URL: https://www.nature.com/articles/s41419-026-08818-7

Molecular Oncology Laboratory (Professor Yuko MURAKAMI-TONAMI)
School of Bioscience and Biotechnology, Tokyo University of Technology
Our laboratory investigates the molecular mechanisms underlying genetic abnormalities in cancer and their impact on cellular functions, with the goal of developing novel therapeutic strategies.
Our research is centered on the concept of synthetic lethality, aiming to identify cancer-specific vulnerabilities that can be exploited therapeutically. We conduct a broad range of studies spanning translational research using small-molecule compounds and nucleic acid therapeutics (siRNA) to fundamental research employing the fission yeast model.

Major Research Topics
1.Elucidation of cell proliferation mechanisms based on synthetic lethality associated with driver gene mutations in malignant mesothelioma.
2.Development of anticancer approaches using small-molecule compounds and siRNA delivery technologies based on synthetic lethality.
3.Investigation of the molecular mechanisms regulating DNA replication, DNA repair, and cell-cycle control, including studies using the fission yeast model.
Laboratory website:
https://murakami-lab.bs.teu.ac.jp/