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

• Published in: Oncogene 2015-01, Vol.34 (1), p.73-83
• Main Authors: Tanaka, I, Osada, H, Fujii, M, Fukatsu, A, Hida, T, Horio, Y, Kondo, Y, Sato, A, Hasegawa, Y, Tsujimura, T, Sekido, Y
• Format: Article
• Language: English
• Subjects: 631/136/2091; 631/67/1641; 631/80/641/83/2360; Adaptor Proteins, Signal Transducing - metabolism; Analysis; Apoptosis; Asbestos; Binding proteins; Cell Adhesion; Cell Biology; Cell growth; Cell Line, Tumor; Cell Proliferation; Cellular signal transduction; Cytoplasm - metabolism; Development and progression; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Human Genetics; Humans; Immunohistochemistry; Internal Medicine; Kinases; Lentivirus; Lentivirus - genetics; LIM Domain Proteins - metabolism; Lung cancer; Lung Neoplasms - metabolism; Medicine; Medicine & Public Health; Mesothelioma; Mesothelioma - metabolism; Mesothelioma, Malignant; Neoplasia; Neurofibromatosis; Neurofibromatosis 2; Neurofibromin 2; Neurofibromin 2 - metabolism; Oncology; original-article; Phenotype; Phenotypes; Phosphoproteins - metabolism; Phosphorylation; Properties; Protein-Serine-Threonine Kinases - metabolism; Proteins; RNA, Small Interfering - metabolism; Signal Transduction; Transcription activation; Transcription Factors; Tumor suppressor genes; Yes-associated protein
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.528

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.