Oncotarget

Research Papers:

TAZ induces lung cancer stem cell properties and tumorigenesis by up-regulating ALDH1A1

Jihang Yu, Adel Alharbi, Hongchao Shan, Yawei Hao, Brooke Snetsinger, Michael J. Rauh and Xiaolong Yang _

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Oncotarget. 2017; 8:38426-38443. https://doi.org/10.18632/oncotarget.16430

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Abstract

Jihang Yu1,*, Adel Alharbi1,2,*, Hongchao Shan1, Yawei Hao1, Brooke Snetsinger1, Michael J Rauh1, Xiaolong Yang1

1Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada

2Department of Laboratory Medicine, Umm Al-Qura University, Makkah, Makkah Province, Saudi Arabia

*These authors contributed equally to this work

Correspondence to:

Xiaolong Yang, email: yangx@queensu.ca

Keywords: Hippo, TAZ, ALDH1A1, lung cancer, cancer stem cells

Received: July 22, 2016     Accepted: March 11, 2017     Published: March 21, 2017

ABSTRACT

Recent studies suggest that lung cancer stem cells (CSCs) may play major roles in lung cancer. Therefore, identification of lung CSC drivers may provide promising targets for lung cancer. TAZ is a transcriptional co-activator and key downstream effector of the Hippo pathway, which plays critical roles in various biological processes. TAZ has been shown to be overexpressed in lung cancer and involved in tumorigenicity of lung epithelial cells. However, whether TAZ is a driver for lung CSCs and tumor formation in vivo is unknown. In addition, the molecular mechanism underlying TAZ-induced lung tumorigenesis remains to be determined. In this study, we provided evidence that constitutively active TAZ (TAZ-S89A) is a driver for lung tumorigenesis in vivo in mice and formation of lung CSC. Further RNA-seq and qRT-PCR analysis identified Aldh1a1, a well-established CSC marker, as critical TAZ downstream target and showed that TAZ induces Aldh1a1 transcription by activating its promoter activity through interaction with the transcription factor TEAD. Most significantly, inhibition of ALDH1A1 with its inhibitor A37 or CRISPR gene knockout in lung cancer cells suppressed lung tumorigenic and CSC phenotypes in vitro, and tumor formation in mice in vivo. In conclusion, this study identified TAZ as a novel inducer of lung CSCs and the first transcriptional activator of the stem cell marker ALDH1A1. Most significantly, we identified ALDH1A1 as a critical meditator of TAZ-induced tumorigenic and CSC phenotypes in lung cancer. Our studies provided preclinical data for targeting of TAZ-TEAD-ALDH1A1 signaling to inhibit CSC-induced lung tumorigenesis in the future.


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