LATS2 is a tumor suppressor gene of malignant mesothelioma.
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 LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 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 LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. 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.
Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Hideki
H
Murakami
Tetsuya
T
Mizuno
Tetsuo
T
Taniguchi
Makiko
M
Fujii
Futoshi
F
Ishiguro
Takayuki
T
Fukui
Shinya
S
Akatsuka
Yoshitsugu
Y
Horio
Toyoaki
T
Hida
Yutaka
Y
Kondo
Shinya
S
Toyokuni
Hirotaka
H
Osada
Yoshitaka
Y
Sekido
D018797:Cell Cycle Proteins / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002882:Chromosomes, Human, Pair 13; D055028:Comparative Genomic Hybridization; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D025581:Neurofibromin 2 / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D014161:Transduction, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D025581:Neurofibromin 2; C415864:SAV1 protein, human; D025521:Tumor Suppressor Proteins; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases