Targeting YAP in malignant pleural mesothelioma

• Published in: Journal of cellular and molecular medicine 2017-11, Vol.21 (11), p.2663-2676
• Main Authors: Zhang, Wen‐Qian, Dai, Yu‐Yuan, Hsu, Ping‐Chih, Wang, Hui, Cheng, Li, Yang, Yi‐Lin, Wang, Yu‐Cheng, Xu, Zhi‐Dong, Liu, Shu, Chan, Geraldine, Hu, Bin, Li, Hui, Jablons, David M., You, Liang
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Antineoplastic Agents - pharmacology; Cancer; Cell Line, Tumor; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Gene Expression Regulation, Neoplastic; Genes, Reporter; Hippo pathway; Humans; Immunohistochemistry; Inhibition; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mesothelioma; Mesothelioma - genetics; Mesothelioma - metabolism; Mesothelioma - pathology; Mesothelioma, Malignant; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original; Phosphoproteins - antagonists & inhibitors; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Porphyrins - pharmacology; Prognosis; Proteins; rho-Associated Kinases - genetics; rho-Associated Kinases - metabolism; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; siRNA; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Spheroids, Cellular - pathology; TEA Domain Transcription Factors; therapeutic target; Transcription; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Verteporfin; YAP; YAP-Signaling Proteins; Yes-associated protein
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.13182

Malignant mesothelioma is an aggressive cancer that is resistant to current therapy. The poor prognosis of mesothelioma has been associated with elevated Yes‐associated protein (YAP) activity. In this study, we evaluated the effect of targeting YAP in mesothelioma. First, we comprehensively studied YAP activity in five mesothelioma cell lines (211H, H2052, H290, MS‐1 and H2452) and one normal mesothelial cell line (LP9). We found decreased phospho‐YAP to YAP protein ratio and consistently increased GTIIC reporter activity in 211H, H2052 and H290 compared to LP9. The same three cell lines (IC50s < 1 μM) were more sensitive than LP9 (IC50 = 3.5 μM) to the YAP/TEAD inhibitor verteporfin. We also found that verteporfin significantly reduced YAP protein level, mRNA levels of YAP downstream genes and GTIIC reporter activity in the same three cell lines, indicating inhibition of YAP signaling by verteporfin. Verteporfin also impaired invasion and tumoursphere formation ability of H2052 and H290. To validate the effect of specific targeting YAP in mesothelioma cells, we down‐regulated YAP by siRNA. We found siYAP significantly decreased YAP transcriptional activity and impaired invasion and tumoursphere formation ability of H2052 and H290. Furthermore, forced overexpression of YAP rescued GTIIC reporter activity and cell viability after siYAP targeting 3′UTR of YAP. Finally, we found concurrent immunohistochemistry staining of ROCK2 and YAP (P < 0.05). Inhibition of ROCK2 decreased GTIIC reporter activity in H2052 and 211H suggesting that Rho/ROCK signaling also contributed to YAP activation in mesothelioma cells. Our results indicate that YAP may be a potential therapeutic target in mesothelioma.