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

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.

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

“…Interestingly, in synovial sarcoma, FOXM1 levels appear to be less uniform, suggesting that they use alternate mechanisms of proliferation control. The Oncomine coexpression analysis tool identified genes whose expression paralleled FOXM1 in STS, and the top 40 genes were compared with established or potential YAP targets identified in the literature (6,16,29) and a microarray dataset of YAP-regulated genes in human malignant mesothelioma cells (10). Of the top 40 genes coexpressed with FOXM1 in the Detwiller et al database, 13 are also putative YAP targets ( Fig.…”

“…For the first time, to our knowledge, we show that YAP interacts with the forkhead box transcription factor FOXM1 to coregulate critical components of sarcomagenesis, specifically in fibrosarcoma, undifferentiated pleomorphic sarcomas, and liposarcomas. (8)(9)(10)(11). Recent studies have revealed that mutations in the Hippo pathway are more common than previously thought (8,12).…”

“…Many YAP/ TEAD targets have been associated with tumor progression, including BIRC5, CCND1, and forkhead box M1 (FOXM1) (6,10,15,16). In particular, YAP/TEAD directly bind the FOXM1 promoter, inducing its expression in a model of malignant mesothelioma (where upstream NF2 mutations are common) (10).…”

“…Many YAP/ TEAD targets have been associated with tumor progression, including BIRC5, CCND1, and forkhead box M1 (FOXM1) (6,10,15,16). In particular, YAP/TEAD directly bind the FOXM1 promoter, inducing its expression in a model of malignant mesothelioma (where upstream NF2 mutations are common) (10). FOXM1 is a winged helix-turn-helix transcription factor important for cell-cycle progression (17), whose activity is inhibited by direct interaction with the p19 ARF (18), p53 (19), and retinoblastoma pathways (20).…”

FoxO1 regulates apoptosis induced by asbestos in the MT-2 human T-cell line

“…Furthermore, molecular analysis of MPM cells revealed several molecules implicated in the development of MPM. In particular, inactivation of the NF2/merlin signaling pathway caused by loss of NF2/merlin, LATS2 or up-regulation of YAP1 (Mizuno et al 2012) in MPM cells. In addition, inactivation of p16/ink4a, inactivation of tumor suppressor PTEN, and somatic mutations of BRCA 1-associated protein-1 (BAP1) were also reported in MPM cells (Kratzke et al 1995;Opitz et al 2008;Bott et al 2011;Testa et al 2011).…”