Data from <i>LATS2</i> Is a Tumor Suppressor Gene of Malignant Mesothelioma

Abstract

<div>Abstract<p>Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the <i>LATS2</i> (<i>large tumor suppressor homolog 2</i>) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of <i>LATS2</i> among 45 MMs. <i>LATS2</i> encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced <i>LATS2</i> in MM cells with its mutation. Transduction of <i>LATS2</i> inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of <i>LATS2</i>. Because <i>NF2</i> is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of <i>LATS2</i> or an upstream regulator of this pathway, Merlin, which is encoded by <i>NF2.</i> Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation. <i>Cancer Res; 71(3); 873–83. ©2011 AACR</i>.</p></div>