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

• Published in: Oncogene Vol. 31; no. 49; pp. 5117 - 5122
• Main Authors: Mizuno, T, Murakami, H, Fujii, M, Ishiguro, F, Tanaka, I, Kondo, Y, Akatsuka, S, Toyokuni, S, Yokoi, K, Osada, H, Sekido, Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06-12-2012; Nature Publishing Group
• Subjects: 631/208/200; 631/80/641/83/2360; 692/420/755; 692/699/67/1641; Apoptosis; Carcinogenesis; Cell activation; Cell Biology; Cell cycle; Cell Cycle - genetics; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell Proliferation; Cell survival; Cyclin D1 - genetics; Development and progression; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Forkhead Box Protein M1; Forkhead Transcription Factors - genetics; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genetic aspects; Genetic regulation; Genetic transcription; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Mesothelioma; Mesothelioma - genetics; Mesothelioma - pathology; Neurofibromatosis; Neurofibromatosis 2; Neurofibromin 2; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncology; Phenotypes; Promoters (Genetics); Properties; Proteins; short-communication; Signal transduction; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptome; Tumors; Up-Regulation; Yes-associated protein; Japan; YAP; Hippo pathway; CCND1; malignant mesothelioma; cell cycle
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.5

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.