Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition

Lei Gao, Yong Hu, Yahui Tian, Zhenzhen Fan, Kun Wang, Hongdan Li, Qian Zhou, Guandi Zeng, Xin Hu, Lei Yu, Shiyu Zhou, Xinyuan Tong, Hsinyi Huang, Haiquan Chen, Qingsong Liu, Wanting Liu, Gong Zhang, Musheng Zeng, Guangbiao Zhou, Qingyu He (), Hongbin Ji () and Liang Chen ()
Additional contact information
Lei Gao: Jinan University
Yong Hu: Jinan University
Yahui Tian: Jinan University
Zhenzhen Fan: Jinan University
Kun Wang: Chinese Academy of Sciences
Hongdan Li: Jinan University
Qian Zhou: Jinan University
Guandi Zeng: Jinan University
Xin Hu: The University of Texas Health Science Center at Houston (UTHealth)
Lei Yu: Capital Medical University
Shiyu Zhou: Chinese Academy of Sciences
Xinyuan Tong: Chinese Academy of Sciences
Hsinyi Huang: Chinese Academy of Sciences
Haiquan Chen: Fudan University Shanghai Cancer Center
Qingsong Liu: Chinese Academy of Sciences
Wanting Liu: Jinan University
Gong Zhang: Jinan University
Musheng Zeng: Sun Yat-sen University Cancer Center
Guangbiao Zhou: Chinese Academy of Medical Sciences and Peking Union Medical College
Qingyu He: Jinan University
Hongbin Ji: Chinese Academy of Sciences
Liang Chen: Jinan University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes remain to be systemically identified for lung cancer. Through the genome-wide screening of tumor-suppressive transcription factors, we demonstrate here that GATA4 functions as an essential tumor suppressor in lung cancer in vitro and in vivo. Ectopic GATA4 expression results in lung cancer cell senescence. Mechanistically, GATA4 upregulates multiple miRNAs targeting TGFB2 mRNA and causes ensuing WNT7B downregulation and eventually triggers cell senescence. Decreased GATA4 level in clinical specimens negatively correlates with WNT7B or TGF-β2 level and is significantly associated with poor prognosis. TGFBR1 inhibitors show synergy with existing therapeutics in treating GATA4-deficient lung cancers in genetically engineered mouse model as well as patient-derived xenograft (PDX) mouse models. Collectively, our work demonstrates that GATA4 functions as a tumor suppressor in lung cancer and targeting the TGF-β signaling provides a potential way for the treatment of GATA4-deficient lung cancer.

Date: 2019
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DOI: 10.1038/s41467-019-09295-7

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