Mesothelioma: A new oncogenic target (YAP1) of the tumor suppressor “Merlin”

In 2004 we found that Merlin, an NF2 gene product, directly inhibits the oncogenic kinase PAK1, and anti-PAK1 drugs such as CEP-1347 and FK228 suppress the growth of NF2-deficient mesothelioma and Schwannoma cell lines.

In summer of 2008, Yoshitaka Sekido’s group at Aichi Cancer Center, Japan, found another target of tumor suppressor “Merlin”, which is also an oncogene product of 65 kDa called YAP1 (YES-associated protein 1). YAP1 is active as a transcription-coactivator (activating a p53-related transcription factor called p73) only when it is localized in nucleus. However, “Merlin” causes the phosphorylation of YAP1 at Ser 127 by the kinase LATS1, and blocks the nuclear localization of YAP1. Thus, “Merlin” is the negative regulator of two oncoproteins, YAP1 and PAK1.

It should be worth noting that unlike PAK1, YAP1 does not bind "Merlin" directly, and nobody knows how "Merlin" activates LATS1. It is possible that PAK1 normally inactivate LATS1, and "Merlin" simply reverses the action of PAK1...

Interestingly, in malignant pleural mesotheliomas (MPMs), YAP1 gene is often over-expressed, and NF2 gene is often deleted (or dysfunctions). This could be explained by the fact that "Merlin" inactivates YAP1 gene somehow.

Since we discovered that “Bio 30”, a CAPE-rich water-miscible extract of propolis from NZ (New Zealand) , suppresses the growth of NF2-deficient Schwannoma cells both in vitro (cell culture) and in vivo (xenograft in mice) by blocking the oncogenic PAK1 pathways, it would be of great interest to examine whether like “Merlin”, Bio 30 causes the phosphorylation of YAP1 at Ser 127, inactivating YAP1. If so, since YAP1 is essential for the growth of these MPMs, Bio 30 could be useful for the treatment of the formidable MPMs, in addition to brain tumors such as NF (neurofibromatosis) and gliomas as well as pancreatic and breast cancers.

Carcinogenesis (PubMed, 2008 Aug 25):

YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation.

Yokoyama T, Osada H, Murakami H, Tatematsu Y, Taniguchi T, Kondo Y, Yatabe Y, Hasegawa Y, Shimokata K, Horio Y, Hida T, Sekido Y.

Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.

We previously reported the results of BAC-array-CGH of malignant pleural mesotheliomas (MPMs), including two cases with high-level amplification in the 11q22 locus. In this study, we found that the YAP1 gene encoding a transcriptional co-activator, was localized in this amplified region and overexpressed in both cases, suggesting it as a candidate oncogene in this region. We analyzed the involvement of YAP1 in MPM proliferation, as well as its functional and physical interaction with Merlin encoded by the neurofibromatosis type 2 (NF2) tumor-suppressor gene, which is frequently mutated in MPMs. YAP1-RNAi suppressed growth of a mesothelioma cell line NCI-H290 with NF2 homozygous deletion, probably through cell-cycle arrest and apoptosis induction, while YAP1 transfection promoted the growth of MeT-5A, an immortalized mesothelial cell line. We also found that the introduction of NF2 into NCI-H290 induced phosphorylation at Ser127 of YAP1, which was accompanied by reduction of nuclear localization of YAP1, whereas nuclear localization of a YAP1 S127A-mutant was not affected. Furthermore, results of immunoprecipitation and in vitro pull-down assays indicated a physical interaction between Merlin and YAP1. These results suggest that YAP1 is involved in mesothelial cell growth, and that the transcriptional co-activator activity of YAP1 is functionally inhibited by Merlin through the induction of phosphorylation and cytoplasmic retention of YAP1. This is the first report of negative-regulatory signaling from Merlin to YAP1 in mammalian cells. Future studies of transcriptional targets of YAP1 in MPMs may shed light on the molecular mechanisms of MPM development and lead to new therapeutic strategies.