NF2 blocks Snail-mediated p53 suppression in mesothelioma

// Jung-Hyun Cho 1 , Su-Jin Lee 1 , Ah-Young Oh 1 , Min-Ho Yoon 1 , Tae-Geun Woo 1 and Bum-Joon Park 1 1 Department of Molecular Biology, Graduated School of System Biology, College of Natural Science, Pusan National University, Busan Correspondence to: Bum-Joon Park, email: // Keywords : mesothelioma, p53, NF2, RKIP, Snail Received : December 31, 2014 Accepted : February 13, 2015 Published : March 12, 2015 Abstract Although asbestos causes malignant pleural mesothelioma (MPM), rising from lung mesothelium, the molecular mechanism has not been suggested until now. Extremely low mutation rate in classical tumor suppressor genes (such as p53 and pRb) and oncogenes (including Ras or myc) indicates that there would be MPM-specific carcinogenesis pathway. To address this, we treated silica to mimic mesothelioma carcinogenesis in mesothelioma and non-small cell lung cancer cell lines (NSCLC). Treatment of silica induced p-Erk and Snail through RKIP reduction. In addition, p53 and E-cadherin were decreased by silica-treatment. Elimination of Snail restored p53 expression. We found that NF2 (frequently deleted in MPM) inhibited Snail-mediated p53 suppression and was stabilized by RKIP. Importantly, GN25, an inhibitor of p53-Snail interaction, induced p53 and apoptosis. These results indicate that MPM can be induced by reduction of RKIP/NF2, which suppresses p53 through Snail. Thus, the p53-Snail binding inhibitor such as GN25 is a drug candidate for MPM.