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-beta 2 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-beta signaling provides a potential way for the treatment of GATA4-deficient lung cancer.
基金：
National Key R&D Program of China [2016YFC0905500]; Guangzhou Research Project of Science and Technology for Citizen Health [201803010124]; NSFCNational Natural Science Foundation of China (NSFC) [81672309, 81430066, 31621003, 91731314, 81872312]; Fundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central Universities [21618326]; National Basic Research Program of ChinaNational Basic Research Program of China [2017YFA0505500]; Strategic Priority Research Program of the Chinese Academy of SciencesChinese Academy of Sciences [XDB19000000]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2015M581673]; Chinese Academy of Science Taiwan Young Scholar Visiting Program [2015TW1SB0001]
第一作者机构：[1]Jinan Univ, Coll Life Sci & Technol, Inst Life & Hlth Engn, Key Lab Funct Prot Res Guangdong Higher Educ, Guangzhou 510632, Guangdong, Peoples R China[2]Beijing Normal Univ, Coll Life Sci, Beijing 100875, Peoples R China
共同第一作者：
通讯作者：
通讯机构：[7]Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Cell Biol, Shanghai 200031, Peoples R China[8]Chinese Acad Sci, Ctr Excellence Mol Cell Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China[9]Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Innovat Ctr Cell Signaling Network, Shanghai 200031, Peoples R China[16]Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200120, Peoples R China
推荐引用方式(GB/T 7714)：
Gao Lei,Hu Yong,Tian Yahui,et al.Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition[J].NATURE COMMUNICATIONS.2019,10:doi:10.1038/s41467-019-09295-7.
APA：
Gao, Lei,Hu, Yong,Tian, Yahui,Fan, Zhenzhen,Wang, Kun...&Chen, Liang.(2019).Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition.NATURE COMMUNICATIONS,10,
MLA：
Gao, Lei,et al."Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition".NATURE COMMUNICATIONS 10.(2019)
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