Our long-term goal is to understand better the cellular processes that regulate metastasis and to develop strategy for intervention of metastasis in patients, and this project aims at understanding the pro-metastatic role of FOG2/GATA3 complex in lung adenocarcinoma metastasis. Given that metastasis is the primary cause of death from lung cancer, the No.1 cause of deaths among all malignancies, our studies will potentially have a tremendous public health impact. On the basis of our recent publication, we hypothesize that GATA3 drives lung adenocarcinoma metastasis by forming transcription complexes with its pro-metastatic transcription co- factors. Our preliminary results showed that FOG2 is such a co-factor. Therefore, the primary objective of this application is to elucidate the role of FOG2 in the regulation of GATA3-dependent metastasis. Our central hypothesis is that the transcription complex formed by FOG2 and GATA3 drives metastasis through transcriptional regulation of pro-metastatic genes in lung adenocarcinoma cells. Given that GATA3 acts as metastasis suppressor in breast tumors, our hypothesis opens a new area of investigation into the role of GATA3, by complexing with its pro-metastatic transcription co-factors (e.g. FOG2 identified by our preliminary studies), as a driver of metastasis. To test our hypothesis, we propose to complete two Specific Aims.
The first Aim will utilize next-generation sequencing technique to identify putative pro-metastatic transcriptional targets for the FOG2/GATA3 complex;and the role of these genes in invasion and metastasis of lung adenocarcinoma cells will be evaluated by an in vitro invasion assay followed by in vivo metastasis studies using syngeneic metastasis model we have developed.
The second Aim will explore several novel mechanisms that regulate FOG2/GATA3 complex: first, we will determine whether the binding of GATA3 to FOG2 is required for EMT, invasion, and metastasis;second, we will determine whether p85? inhibits invasion by binding to FOG2 and sequestering FOG2 in the cytosol, preventing its nuclear translocation;and third, we will determine whether AKT directly phosphorylates and activates FOG2. We expect that the successful completion of this project will advance our current understanding of the mechanisms of lung cancer metastasis and found the basis for developing novel therapeutic strategies.

Public Health Relevance

Lung cancer is the leading cause of cancer-related death in the United States, and metastasis is the primary cause of lung cancer patients'death. For patients who have developed metastases, treatment options are limited, and the outcome has been disappointing, partly due to the insufficient understanding of the biology of metastasis. As such, there is a critical need for elucidating the biological processes that regulate metastasis, which will not only facilitate the discovery of novel therapeutic targets, but also improve our capability to manage this deadly disease. Our preliminary data suggests the FOG2/GATA3 transcriptional complex promotes metastasis by transcriptionally regulating pro-metastatic genes in lung adenocarcinoma cells. Our proposed studies are designed to use the models we have generated as a platform on which to first, elucidate the novel mechanisms by which the FOG2/GATA3 complex is regulated;and second, identify the FOG2/GATA3-regulated pro-metastatic genes, which will found the basis for developing novel therapeutic targets for the treatment of lung cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Ault, Grace S
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Mayo Clinic, Rochester
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Liu, Wei; Zhang, Ting; Guo, Lixia et al. (2018) Lysyl hydroxylases are transcription targets for GATA3 driving lung cancer cell metastasis. Sci Rep 8:11905
Zhang, Ting; Guo, Lixia; Wang, Yuanyuan et al. (2018) Macroautophagy Regulates Nuclear NOTCH1 Activity Through Multiple p62 Binding Sites. IUBMB Life 70:985-994
Zhang, Ting; Guo, Lixia; Creighton, Chad J et al. (2016) A genetic cell context-dependent role for ZEB1 in lung cancer. Nat Commun 7:12231
Guo, Lixia; Wang, Jingyu; Zhang, Ting et al. (2016) Glypican-5 is a tumor suppressor in non-small cell lung cancer cells. Biochem Biophys Rep 6:108-112
Chen, Yulong; Terajima, Masahiko; Yang, Yanan et al. (2015) Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. J Clin Invest 125:1147-62
Guo, Lixia; Wang, Jingyu; Yang, Ping et al. (2015) MicroRNA-200 promotes lung cancer cell growth through FOG2-independent AKT activation. IUBMB Life 67:720-5