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YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation Through a COX-2−EGFR Signaling Axis

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YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation Through a COX-2−EGFR Signaling Axis Published OnlineFirst May 23, 2016; DOI: 10.1158/0008-5472.CAN-15-1144 Cancer Molecular and Cellular Pathobiology Research YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2–EGFR Signaling Axis William Guerrant1, Smitha Kota1, Scott Troutman1, Vinay Mandati1, Mohammad Fallahi2, Anat Stemmer-Rachamimov3, and Joseph L. Kissil1 Abstract The Hippo–YAP pathway has emerged as a major driver of survival, proliferation, and tumor growth in vivo.Moreover, tumorigenesis in many human cancers. YAP is a transcrip- YAP promotes transcription of several targets including tional coactivator and while details of YAP regulation are PTGS2, which codes for COX-2, a key enzyme in prostaglan- quickly emerging, it remains unknown what downstream din biosynthesis, and AREG, which codes for the EGFR ligand, targets are critical for the oncogenic functions of YAP. To amphiregulin. Both AREG and prostaglandin E2 converge to determine the mechanisms involved and to identify disease- activate signaling through EGFR. Importantly, treatment with relevant targets, we examined the role of YAP in neurofibro- the COX-2 inhibitor celecoxib significantly inhibited the matosis type 2 (NF2) using cell and animal models. We found growth of NF2-null Schwann cells and tumor growth in a that YAP function is required for NF2-null Schwann cell mouse model of NF2. Cancer Res; 76(12); 1–13. Ó2016 AACR. Introduction refs. 5, 6). Additional evidence for an oncogenic role of YAP in human tumors stems from findings demonstrating ampli- The Hippo–YAP signaling pathway has emerged as a major fication of genomic region 11q22, to which YAP localizes, in driver of tumorigenesis and metastasis in a wide spectrum of breast cancer and significant upregulation of YAP expression human cancers (1–3). The core of the pathway is composed of a in breast, ovarian, lung, pancreatic, colorectal, and liver can- well-defined kinase cascade composed of the MST1/2 kinases that cers (7, 8). More recent studies have shown that YAP can form a complex with the scaffold protein WW45 and phosphor- function as an oncogene in tumors that are addicted to KRAS. ylate the LATS1/2 kinases. Phosphorylated LATS1/2, in complex Specifically, in models of KRAS-addicted tumors (pancreatic with Mob1, bind and phosphorylate YAP, a transcriptional co- and lung adenocarcinoma), the inhibition of KRAS leads to activator. The phosphorylation of YAP creates a binding site for cell death, which can be rescued by YAP activation (9, 10). 14-3-3 and this prevents p-YAP from entering into the nucleus Finally, genetic evidence for an oncogenic role for YAP in where it can form transcriptionally active complexes with TEADs human cancer comes from two diseases, uveal melanoma and and other transcription factors to drive the expression of propro- neurofibromatosis type 2 (NF2). In uveal melanoma, 80% of liferative or antiapoptotic genes such as CTGF, Cyr61, Axl, Myc, patients harbor mutations in the GNAQ (Gq) and GNA11 and BIRC5 (4). (G11) genes, which code for alpha subunits of heterotrimeric As a regulator of cell fate, proliferation, and death, YAP can G proteins. Previous work had indicated YAP can be activated function as an oncogene. Several examples exist showing that by mutated Gq/11 (11), and subsequently, it was found that YAP overexpression drives tumorigenesis, including mouse mutated Gq/11 oncogenic function is mediated via YAP, thus models in which liver-specific expression of an activated allele implicating YAP as a potential therapeutic target in uveal of YAP or knockout of the MST1 and MST2 alleles in the liver melanoma (12, 13). lead to development of hepatocellular carcinoma (HCC; NF2 is an inherited disorder with an incidence of approxi- mately 1 in 30,000 births, caused by germline mutations of the NF2 1Department of Cancer Biology, The Scripps Research Institute, Jupi- gene. The disease is characterized mainly by development ter, Florida. 2Informatics Core, The Scripps Research Institute, Jupiter, of schwannomas of the eighth cranial nerve (14). The NF2 3 Florida. Department of Pathology, Massachusetts General Hospital, tumor suppressor gene encodes a 69-kDa protein called Merlin Boston, Massachusetts. thathasbeenshowntofunctionasaregulatorofmultiple Note: Supplementary data for this article are available at Cancer Research signaling pathways at the cell membrane and to possess nuclear Online (http://cancerres.aacrjournals.org/). functions. Merlin was originally shown to function upstream of Corresponding Author: Joseph L. Kissil, Scripps Research Institute, 130 Scripps Hippo in flies and subsequently in mammalian cells. A number Way, Jupiter, FL 33458. Phone: 561-228-2170; Fax: 561-228-2175; E-mail: of studies demonstrated that Merlin and YAP function antag- [email protected] onistically, including in vivo studies in which liver-specific doi: 10.1158/0008-5472.CAN-15-1144 knockout of Yap was sufficient to rescue HCC driven by inac- Ó2016 American Association for Cancer Research. tivation of the Nf2 gene (15). www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst May 23, 2016; DOI: 10.1158/0008-5472.CAN-15-1144 Guerrant et al. Mechanistic details of the function of Merlin have emerged eration Assay (Millipore) was used according to the manufac- from studies that demonstrated Merlin acts synergistically with a turer's instructions. Statistical significance was determined by a newly identified Hippo pathway component, Kibra, to promote two-tailed Student t test. Each condition at each time point LATS1/2 phosphorylation (16) and regulate the spatial organi- represents the mean of three experiments in triplicate for a total zation of Hippo pathway components at the cell membrane of 9 wells. bydirectlybindingtoLATS1/2andrecruitingittotheplasma membrane, where it is phosphorylated and activated by a MST- Determination of caspase activity WW45 complex (17). Merlin has also been shown to have a Measurement of caspase-dependent cell death was achieved nuclear function as an inhibitor of the E3 ubiquitin ligase through the use of the Caspase-Glo 3/7 assay following the CRL4DCAF1 (18). Recent studies suggest that CRL4DCAF1 pro- manufacturer's instructions (Promega). Briefly, cells were seed- motes YAP- and TEAD-dependent transcription by inhibition of ed into white, opaque 96-well culture plates at 1,500 cells per LATS1/2 in the nucleus, and analysis of patient samples indi- well and transfected with control or YAP siRNAs. Caspase-Glo cates that this pathway operates in NF2-mutant tumors (19). reagent was added at 24 or 48 hours and incubated at room Thus, while the evidence cited above strongly suggests that YAP temperature for 30 minutes, after which the luminescence was function is required downstream of NF2 loss of function in measured. tumorigenesis, the mechanisms underlying the requirement for YAP and for which downstream targets are critical to the onco- RNA-Seq genic functions of YAP remain unknown. To identify these SC4 cells were transfected with control or YAP SMARTpool mechanisms and identify disease-relevant targets, we employed siRNA for 48 hours, and total RNA was extracted using TRIzol a combination of cell-based and in vivo approaches. Our findings reagent. For analysis, the sequencing reads in color space were indicate that YAP function is required in NF2-null Schwann cells mapped to the mm9 genome using Tophat (23). The number of fi to promote cell survival through regulation of an EGFR signaling reads falling into each gene de ned in the RefSeq gene annota- fi axis via transcriptional regulation of prostaglandin endoperoxide tions was quanti ed using HTSeq-count (24). The DESeq soft- ware (24) was used to detect differentially expressed genes synthase 2 (COX-2) and prostaglandin E2 (PGE2) production. Importantly, our findings suggest that treatment with COX-2 between samples. Samples from three independent experiments fi inhibitors could prove beneficial in slowing the growth rates of were sequenced, combined, and analyzed to produce the nal NF2-associated schwannomas. DESeq data. The RNA-Seq data are publicly available through the NCBI GEO database with accession number GSE61528. Materials and Methods RT-PCR Animal experiments RNAs were extracted using the Qiagen RNeasy Kit and reverse- All animal experiments complied with NIH guidelines and transcribed into cDNA with the SuperScript III Kit (Life Technol- were approved by The Scripps Research Institutional Animal ogies). qPCR was performed with SYBR Green (Applied Biosys- Care and Use Committee. A total of 5 Â 104 SC4-Luc pLKO or tems). Relative gene expression between control and YAP-KD was À SC4-Luc pLKO-YAP cells were injected intraneurally into calculated with the 2 DDCT method (25). For complete primer the sciatic nerves of NOD/SCID mice (6–8 weeks old). Tumor sequences, please see Supplementary Table S2. progression was monitored by bioluminescence imaging on an IVIS-200 system (Xenogen). Treatment was commenced after AREG ELISA detection of signal correlating to tumor sizes of 1 to 2 mm3 Cell media from SC4 and HEI-193 cells treated with the (total flux 106 photons/s). For drug treatment, celecoxib indicated siRNA's was collected and diluted 2-fold with provided (Cayman Chemical) was diluted in vehicle (22.2:66.6:11.2, assay buffer (Mouse AREG ELISA and Human AREG ELISA, ethanol:PEG300:water) to a final dose of 100 mg/kg and Raybiotech). Secreted AREG concentrations were assayed for three administered by oral gavage, daily. Control mice received independent experiments in triplicate, according to manufac- vehicle/DMSO mixture. turer's instructions. AREG concentrations were determined by comparing recorded absorbance readings to a standard curve of Cell lines diluted AREG. SC4 Nf2-null mouse Schwann cells and HEI-193 human NF2- mutant Schwann cells were obtained in 2010 and previously Results described (20, 21). HSC2l cells were obtained from the labora- YAP is required for NF2-null Schwann cell proliferation, tory of Dr.
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