Trichostatin A suppresses lung adenocarcinoma development in Grg1 overexpressing transgenic mice

• Published in: Biochemical and biophysical research communications Vol. 463; no. 4; pp. 1230 - 1236
• Main Authors: Liu, Ju, Li, Yan, Dong, Fengyun, Li, Liqun, Masuda, Takahiro, Allen, Thaddeus D., Lobe, Corrinne G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.08.2015
• Subjects: 60 APPLIED LIFE SCIENCES; Adenocarcinoma - genetics; Adenocarcinoma - prevention & control; Animals; CARCINOMAS; Cell Line, Tumor; Co-Repressor Proteins - genetics; DMSO; ErbB1; ErbB2; FIBROBLASTS; Genes, erbB-1; Genes, erbB-2; Grg1; GROWTH FACTORS; Humans; Hydroxamic Acids - pharmacology; IMPEDANCE; IN VIVO; INHIBITION; Lung adenocarcinoma; Lung Neoplasms - genetics; Lung Neoplasms - prevention & control; LUNGS; Mice; Mice, Transgenic; ONCOGENES; RECEPTORS; SIGNALS; SUBSTRATES; TRANSGENIC MICE; Trichostatin A; VEINS; TSA; ErbB2; FGF; ErbB1; DMSO; VEGF; Transgenic mice; ECIS; Lung adenocarcinoma; TLE; hPLAP; EGFR; Grg1; IRES; HUVEC; TEER; Trichostatin A; ErbB1/2; HDAC
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.06.090

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. •TSA suppresses lung tumorigenesis in Grg1 overexpressing transgenic mice.•TSA does not affect overall Grg1 protein levels in the mice and in A549 cells.•TSA reduces ErbB1 and ErbB2 expression in the mice and in A549 cells.•Lapatinib masks TSA-induced inhibition of A549 cell proliferation and migration.•TSA inhibits VEGF signaling, but not basic FGF signaling.