Identifying the Molecular Mechanism of TAZ-Induced Lung Tumorigenesis

The transcriptional co-activator with PDZ-binding domain (TAZ) is a transcriptional co-activator and downstream component of the tumor suppressor Hippo pathway that plays critical roles in organ size control, stem cell self-renewal, tumorigenesis and drug resistance. Recently, TAZ has been identified as a novel oncogene that is overexpressed in non-small cell lung cancer (NSCLC) cells and mediates their proliferation, transformation and tumorigenesis. However, the molecular mechanism underlying TAZ-induced tumorigenesis remains largely unknown. In this study, we first established an in vivo xenograft mouse model by overexpressing the constitutively active TAZ-S89A in E10 (mouse) and HBE135 (human) immortalized lung epithelial cells. Next, the gene expression profile of this model was analyzed by performing next-generation sequencing (RNA-seq) which led to identifying several novel genes transcriptionally upregulated by TAZ such as INHBA, KLF5, BMPs, FGFs, etc. Interestingly, we identified PI3K and TGF-ß signaling pathways as mediators of TAZ-induced cell proliferation and transformation, which were inhibited by using small molecule inhibitors specifically targeting these two signaling pathways. In addition, TAZ-induced cell proliferation and transformation were suppressed by disrupting the interaction between TAZ and its major binding transcription factor TEAD. Together, our study shows for the first time a new mechanism linking PI3K and TGF-ß pathways to TAZ-induced cell transformation, suggesting TAZ as a therapeutic target for NSCLC.

Department dc:contributor.department

Pathology and Molecular Medicine

Year dc:date.issued

2014

Author dc:creator

• Alharbi, Adel

Advisor dc:contributor.supervisor

• Yang, Xiaolong

• TAZ
• Tumorigenesis
• Lung Cancer
• Hippo Pathway

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1974/12464

OAI identifier oai:identifier

oai:queensu.scholaris.ca:1974/12464