Abstract
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.
Highlights
Malignant pleural mesothelioma (MPM) is a very aggressive form of cancer that affects the pleura
Yes-associated protein (YAP) activity, GTIIC reporter activity and sensitivity to the YAP inhibitor verteporfin increased in several mesothelioma cell lines
We found that the YAP phosphorylation level to total YAP level ratio was significantly reduced in three mesothelioma cell lines (211H, H2052 and H290) compared with LP9 (Fig. 1A and B)
Summary
Malignant pleural mesothelioma (MPM) is a very aggressive form of cancer that affects the pleura. Genetic inactivation status of LATS2, SAV1 and RASSF has been identified in several mesothelioma cell lines and clinical samples [12, 13]. Deletion of these molecules caused by genetic inactivation leads to constitutive YAP activation and induces the oncogenic transformation in cooperation with distinct transcription factors such as TEAD family members (TEAD1-4) [14,15,16,17]. Primary human mesothelioma samples from 60 patients were fixed in formalin and embedded in paraffin in 4-lm tissue microarray sections.
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