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YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes

Oncogene volume 31, pages 5117–5122 (2012)Cite this article

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Abstract

Malignant mesothelioma (MM) shows frequent inactivation of the neurofibromatosis type 2 (NF2) –tumor-suppressor gene. Recent studies have documented that the Hippo signaling pathway, a downstream cascade of Merlin (a product of NF2), has a key role in organ size control and carcinogenesis by regulating cell proliferation and apoptosis. We previously reported that MMs show overexpression of Yes-associated protein (YAP) transcriptional coactivator, the main downstream effector of the Hippo signaling pathway, which results from the inactivation of NF2, LATS2 and/or SAV1 genes (the latter two encoding core components of the mammalian Hippo pathway) or amplification of YAP itself. However, the detailed roles of YAP remain unclear, especially the target genes of YAP that enhance MM cell growth and survival. Here, we demonstrated that YAP-knockdown inhibited cell motility, invasion and anchorage-independent growth as well as cell proliferation of MM cells in vitro. We analyzed genes commonly regulated by YAP in three MM cell lines with constitutive YAP-activation, and found that the major subsets of YAP-upregulating genes encode cell cycle regulators. Among them, YAP directly induced the transcription of CCND1 and FOXM1, in cooperation with TEAD transcription factor. We also found that knockdown of CCND1 and FOXM1 suppressed MM cell proliferation, although the inhibitory effects were less evident than those of YAP knockdown. These results indicate that constitutive YAP activation in MM cells promotes cell cycle progression giving more aggressive phenotypes to MM cells.

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Acknowledgements

We thank Ms Mika Yamamoto for her excellent technical assistance. This work was supported in part by a Special Coordination Fund for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology of Japan (H18-1-3-3-1), KAKENHI (18390245, 22300338), Grant-in-Aid for Third-Term Comprehensive Control Research for Cancer from the Ministry of Health, Labor and Welfare of Japan, the Takeda Science Foundation and the Kobayashi Foundation for Cancer Research.

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Authors and Affiliations

  1. Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan

    T Mizuno, H Murakami, M Fujii, F Ishiguro, I Tanaka, Y Kondo, H Osada & Y Sekido

  2. Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

    T Mizuno, F Ishiguro & K Yokoi

  3. Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan

    S Akatsuka & S Toyokuni

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

    H Osada & Y Sekido

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  1. T Mizuno
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  2. H Murakami
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  3. M Fujii
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Correspondence to Y Sekido.

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Mizuno, T., Murakami, H., Fujii, M. et al. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes. Oncogene 31, 5117–5122 (2012). https://doi.org/10.1038/onc.2012.5

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