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- Title
Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition.
- Authors
Gao, Lei; Hu, Yong; Tian, Yahui; Fan, Zhenzhen; Wang, Kun; Li, Hongdan; Zhou, Qian; Zeng, Guandi; Hu, Xin; Yu, Lei; Zhou, Shiyu; Tong, Xinyuan; Huang, Hsinyi; Chen, Haiquan; Liu, Qingsong; Liu, Wanting; Zhang, Gong; Zeng, Musheng; Zhou, Guangbiao; He, Qingyu
- 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. The tumor suppressor GATA4 is frequently epigenetically silenced in lung cancer. In this study, Gao et al. demonstrate that GATA4 regulates the expression of TGFBR2 and that TGFRB1 inhibitors can synergise with chemotherapeutics to inhibit the growth of GATA4-deficient tumors in mice.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-09295-7