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LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade

Oncogene volume 34, pages 73–83 (2015)Cite this article

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Abstract

Malignant mesothelioma (MM) is one of the most aggressive neoplasms usually associated with asbestos exposure and is highly refractory to current therapeutic modalities. MMs show frequent activation of a transcriptional coactivator Yes-associated protein (YAP), which is attributed to the neurofibromatosis type 2 (NF2)–Hippo pathway dysfunction, leading to deregulated cell proliferation and acquisition of a malignant phenotype. However, the whole mechanism of disordered YAP activation in MMs has not yet been well clarified. In the present study, we investigated various components of the NF2-Hippo pathway, and eventually found that MM cells frequently showed downregulation of LIM-domain protein AJUBA, a binding partner of large tumor suppressor type 2 (LATS2), which is one of the last-step kinases of the NF2-Hippo pathway. Although loss of AJUBA expression was independent of the alteration status of other Hippo pathway components, MM cell lines with AJUBA inactivation showed a more dephosphorylated (activated) level of YAP. Immunohistochemical analysis showed frequent downregulation of AJUBA in primary MMs, which was associated with YAP constitutive activation. We found that AJUBA transduction into MM cells significantly suppressed promoter activities of YAP-target genes, and the suppression of YAP activity by AJUBA was remarkably canceled by knockdown of LATS2. In connection with these results, transduction of AJUBA-expressing lentivirus significantly inhibited the proliferation and anchorage-independent growth of the MM cells that harbored ordinary LATS family expression. Taken together, our findings indicate that AJUBA negatively regulates YAP activity through the LATS family, and inactivation of AJUBA is a novel key mechanism in MM cell proliferation.

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Acknowledgements

This work was supported in part by KAKENHI (24650650, 25290053), Grants-in-Aid for Third-Term Comprehensive Control Research for Cancer from the Ministry of Health, Labor and Welfare of Japan, P-DIRECT and the Takeda Science Foundation (YS). We thank Dr Adi F Gazdar for the cell lines and Mari Kizuki and Miwako Nishizawa for their excellent technical assistance. IT was supported by the Foundation for Promotion of Cancer Research.

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  1. I Tanaka: Awardee of Research Resident Fellowship from the Foundation for Promotion of Cancer Research.

Authors and Affiliations

  1. Department of Thoracic Oncology Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan

    I Tanaka, H Osada, M Fujii, A Fukatsu, Y Kondo & Y Sekido

  2. Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

    I Tanaka & Y Hasegawa

  3. Department of Cancer Genetics, Program in Function Construction Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

    H Osada, A Fukatsu & Y Sekido

  4. Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan

    T Hida & Y Horio

  5. Department of Pathology, Hyogo College of Medicine, Nishinomiya, Japan

    A Sato & T Tsujimura

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Tanaka, I., Osada, H., Fujii, M. et al. LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade. Oncogene 34, 73–83 (2015). https://doi.org/10.1038/onc.2013.528

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