Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition
Gao, Lei1,2; Hu, Yong1; Tian, Yahui1; Fan, Zhenzhen1,3; Wang, Kun4; Li, Hongdan1; Zhou, Qian1; Zeng, Guandi1; Hu, Xin5; Yu, Lei6; Zhou, Shiyu7,8,9; Tong, Xinyuan7,8,9,10; Huang, Hsinyi7,8,9; Chen, Haiquan11; Liu, Qingsong12; Liu, Wanting1; Zhang, Gong1; Zeng, Musheng13; Zhou, Guangbiao14,15; He, Qingyu1; Ji, Hongbin7,8,9,16; Chen, Liang1

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.

Indexed BySCI
Funding ProjectNational Key R&D Program of China[2016YFC0905500] ; Guangzhou Research Project of Science and Technology for Citizen Health[201803010124] ; NSFC[81672309] ; NSFC[81430066] ; NSFC[31621003] ; NSFC[91731314] ; NSFC[81872312] ; Fundamental Research Funds for the Central Universities[21618326] ; National Basic Research Program of China[2017YFA0505500] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB19000000] ; China Postdoctoral Science Foundation[2015M581673] ; Chinese Academy of Science Taiwan Young Scholar Visiting Program[2015TW1SB0001]
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000463984400014
Citation statistics
Cited Times:4[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Corresponding AuthorHe, Qingyu; Ji, Hongbin; Chen, Liang
Affiliation1.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
3.China Agr Univ, Coll Biol Sci, Beijing 100094, Peoples R China
4.Chinese Acad Sci, Inst Automat, Key Lab Mol Imaging, Beijing 100190, Peoples R China
5.Univ Texas Hlth Sci Ctr Houston UTHlth, 2450 Holcombe Blvd,Suite 1, Houston, TX 77021 USA
6.Capital Med Univ, Beijing Tongren Hosp, Beijing 100730, Peoples R China
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
10.Univ Chinese Acad Sci, Beijing, Peoples R China
11.Fudan Univ, Dept Thorac Surg, Shanghai Canc Ctr, Shanghai 200032, Peoples R China
12.Chinese Acad Sci, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China
13.Sun Yat Sen Univ, Ctr Canc, Dept Expt Res, Guangzhou, Guangdong, Peoples R China
14.Chinese Acad Med Sci, Natl Canc Ctr, Canc Hosp, State Key Lab Mol Oncol, Beijing 100021, Peoples R China
15.Peking Union Med Coll, Beijing 100021, Peoples R China
16.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200120, Peoples R China
Recommended Citation
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(1):1665.
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(1),1665.
MLA Gao, Lei,et al."Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition".NATURE COMMUNICATIONS 10.1(2019):1665.
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