YAP and TAZ modulate cell phenotype in a subset of small cell lung cancer

• Published in: Cancer science Vol. 107; no. 12; pp. 1755 - 1766
• Main Authors: Horie, Masafumi, Saito, Akira, Ohshima, Mitsuhiro, Suzuki, Hiroshi I., Nagase, Takahide
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2016; John Wiley and Sons Inc
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; AJUBA; Antineoplastic Agents - pharmacology; ASCL1 protein; Cell adhesion & migration; Cell Adhesion - genetics; Cell Line, Tumor; Chemoresistance; Cluster Analysis; Cytology; Datasets; DNA microarrays; Drug Resistance, Neoplasm - genetics; Encyclopedias; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genomes; Growth patterns; Hematology; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Laminin; LIM Domain Proteins - genetics; LIM Domain Proteins - metabolism; LIM protein; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Malignancy; Medical prognosis; Metastases; Morphology; Mutation; Ontology; Original; Phenotype; Phenotypes; Phosphoproteins - genetics; Phosphoproteins - metabolism; SCLC; Small cell lung carcinoma; Small Cell Lung Carcinoma - genetics; Small Cell Lung Carcinoma - metabolism; Small Cell Lung Carcinoma - pathology; TAZ; Topotecan - pharmacology; Trans-Activators; Transcription; Transcription Factors; Transcriptome; YAP; Yes-associated protein; United States > US; Japan; SCLC; YAP; morphology; TAZ; AJUBA
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.13078

Small cell lung cancer (SCLC) is a highly aggressive and metastatic malignancy that shows rapid development of chemoresistance and a high rate of recurrence. Recent genome and transcriptome studies have provided the whole landscape of genomic alterations and gene expression changes in SCLC. In light of the inter‐individual heterogeneity of SCLC, subtyping of SCLC might be helpful for prediction of therapeutic response and prognosis. Based on the transcriptome data of SCLC cell lines, we undertook transcriptional network‐defined SCLC classification and identified a unique SCLC subgroup characterized by relatively high expression of Hippo pathway regulators Yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ) (YAP/TAZ subgroup). The YAP/TAZ subgroup displayed adherent cell morphology, lower expression of achaete‐scute complex homolog 1 (ASCL1) and neuroendocrine markers, and higher expression of laminin and integrin. YAP knockdown caused cell morphological alteration reminiscent of floating growth pattern in many SCLC cell lines, and microarray analyses revealed a subset of genes regulated by YAP, including Ajuba LIM protein (AJUBA). AJUBA also contributed to cell morphology regulation. Of clinical importance, SCLC cell lines of the YAP/TAZ subgroup showed unique patterns of drug sensitivity. Our findings shed light on a subtype of SCLC with YAP and TAZ expression, and delineate molecular networks underlying the heterogeneity of SCLC. Subtypes of SCLC cell lines defined by expression patterns of transcription factors. Two‐dimensional hierarchical clustering of expression levels of 1520 transcription factors in SCLC cell lines.