Trichostatin A suppresses lung adenocarcinoma development in Grg1 overexpressing transgenic mice
Ju Liu1, Yan Li2, Fengyun Dong3
1Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, China; Molecular and Cellular Biology Division, Sunnybrook Health Science Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
Abstract:
Trichostatin A (TSA) is a histone deacetylase inhibitor and a potential therapeutic for various malignancies. The in vivo effect of TSA, however, has not been investigated in a transgenic lung cancer model. Previously, we generated transgenic mice with overexpression of Groucho-related-gene 1 (Grg1) and these mice all developed mucinous lung adenocarcinoma. Grg1 is a transcriptional co-repressor protein, the function of which is thought to depend on HDAC activity. However, functions outside the nucleus have also been proposed. We tested the supposition that Grg1-induced tumorigenesis is HDAC-dependent by assaying the therapeutic effect of TSA in the Grg1 transgenic mouse model. We found that TSA significantly inhibited lung tumorigenesis in Grg1 transgenic mice (p < 0.01). TSA did not affect overall Grg1 protein levels, but instead reduced ErbB1 and ErbB2 expression, which are upregulated by Grg1 in the absence of TSA. We confirmed this effect in A549 cells. Furthermore, lapatinib, an inhibitor of both ErbB1 and ErbB2, effectively masked the effect of TSA on the inhibition of A549 cell proliferation and migration, suggesting TSA does work, at least in part, by downregulating ErbB receptors. We additionally found that TSA reduced the expression of VEGF and VEGFR2, but not basic FGF and FGFR1. Our findings indicate that TSA effectively inhibits Grg1-induced lung tumorigenesis through the down-regulation of ErbB1 and ErbB2, as well as reduced VEGF signaling. This suggests TSA and other HDAC inhibitors could have therapeutic value in the treatment of lung cancers with Grg1 overexpression.
Insights
Trichostatin A (TSA) effectively inhibits lung cancer in a Grg1 transgenic mouse model by reducing ErbB1/ErbB2 and VEGF signaling, suggesting its therapeutic potential for lung adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Trichostatin A (TSA) is a histone deacetylase inhibitor with potential anti-cancer properties.
- Groucho-related-gene 1 (Grg1) overexpression induces mucinous lung adenocarcinoma in a transgenic mouse model.
- The role of histone deacetylase (HDAC) activity in Grg1-induced tumorigenesis is not fully understood.
Purpose of the Study:
- To investigate the in vivo therapeutic effect of TSA in a Grg1 transgenic lung cancer model.
- To determine if Grg1-induced lung tumorigenesis is dependent on HDAC activity.
- To elucidate the molecular mechanisms by which TSA exerts its anti-tumor effects in this model.
Main Methods:
- Treatment of Grg1 transgenic mice with TSA.
- Analysis of tumor development and progression in treated and untreated mice.
- Assessment of key protein expression levels (Grg1, ErbB1, ErbB2, VEGF, VEGFR2, FGF, FGFR1) in mouse lung tissue and A549 cells.
- Inhibition studies using lapatinib, an ErbB1/ErbB2 inhibitor, in A549 cells.
Main Results:
- TSA significantly inhibited lung tumorigenesis in Grg1 transgenic mice.
- TSA did not alter overall Grg1 protein levels but reduced ErbB1 and ErbB2 expression.
- TSA decreased VEGF and VEGFR2 expression, but not basic FGF or FGFR1.
- Lapatinib partially reversed TSA's inhibitory effects on A549 cell proliferation and migration.
Conclusions:
- TSA effectively inhibits Grg1-induced lung tumorigenesis in vivo.
- The anti-tumor effects of TSA are mediated, at least in part, by down-regulating ErbB1/ErbB2 and VEGF signaling pathways.
- TSA and other HDAC inhibitors show therapeutic promise for lung cancers with Grg1 overexpression.
More Related Videos
06:03Orthotopic Transplantation of Syngeneic Lung Adenocarcinoma Cells to Study PD-L1 Expression
Published on: January 19, 2019
11:31Using Micro-computed Tomography for the Assessment of Tumor Development and Follow-up of Response to Treatment in a Mouse Model of Lung Cancer
Published on: May 20, 2016