Identifying the Molecular Mechanism of TAZ-Induced Lung Tumorigenesis
type: CreativeWork
description: 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.
abstract: 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.
author: Alharbi, Adel
language: eng
keywords: TAZ, Tumorigenesis, Lung Cancer, Hippo Pathway
date published: 2014-09-17
date modified: 2026-07-27T20:35:39Z
provider: Queens University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Queens University

PropertyValue
property ID: Handle
value: http://hdl.handle.net/1974/12464