YAP promotes malignant progression of Lkb1-deficient lung adenocarcinoma through downstream regulation of survivin.

Abstract

The serine/threonine kinase LKB1 is a well-characterized tumor suppressor that governs diverse cellular processes, including growth, polarity, and metabolism. Somatic-inactivating mutations in LKB1 are observed in about 15% to 30% of non-small cell lung cancers (NSCLC). LKB1 inactivation confers lung adenocarcinomas (ADC) with malignant features that remain refractory to therapeutic intervention. YAP activation has been linked to LKB1 deficiency, but the role of YAP in lung ADC formation and progression is uncertain. In this study, we showed that ectopic expression of YAP in type II alveolar epithelial cells led to hyperplasia in mouse lungs. YAP overexpression in the Kras(G12D) lung cancer mouse model accelerated lung ADC progression. Conversely, YAP deletion dramatically delayed the progression of lung ADC in LKB1-deficient Kras(G12D) mice. Mechanistic studies identified the antiapoptotic oncoprotein survivin as the downstream mediator of YAP responsible for promoting malignant progression of LKB1-deficient lung ADC. Collectively, our findings identify YAP as an important contributor to lung cancer progression, rationalizing YAP inhibition in the context of LKB1 deficiency as a therapeutic strategy to treat lung ADC.

• Authors: Wenjing Zhang, Yijun Gao, Fuming Li, Xinyuan Tong, Yan Ren, Xiangkun Han, Shun Yao, Fei Long, Zhongzhou Yang, Hengyu Fan, Lei Zhang, Hongbin Ji
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 21 Pg. 4450-7 (Nov 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 26363011 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Adaptor Proteins, Signal Transducing
• Birc5 protein, mouse
• Cell Cycle Proteins
• Inhibitor of Apoptosis Proteins
• Phosphoproteins
• Repressor Proteins
• Survivin
• YAP-Signaling Proteins
• Yap1 protein, mouse
• Protein Serine-Threonine Kinases
• Stk11 protein, mouse
• AMP-Activated Protein Kinases
• Proto-Oncogene Proteins p21(ras)

Topics

• AMP-Activated Protein Kinases
• Adaptor Proteins, Signal Transducing (genetics, physiology)
• Adenocarcinoma (genetics, pathology)
• Adenocarcinoma of Lung
• Animals
• Carcinoma, Non-Small-Cell Lung (genetics, pathology)
• Cell Cycle Proteins
• Cell Line, Tumor
• Disease Progression
• Enzyme Activation
• Genes, Tumor Suppressor
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Lung (pathology)
• Lung Neoplasms (genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Nude
• Neoplasm Transplantation
• Phosphoproteins (genetics, physiology)
• Protein Serine-Threonine Kinases (genetics)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Repressor Proteins (metabolism)
• Survivin
• Transplantation, Heterologous
• YAP-Signaling Proteins