title: Trichostatin A suppresses lung adenocarcinoma development in Grg1 overexpressing transgenic mice.
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.
authors.affiliation: Medical 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. Electronic address: ju.liu@sdu.edu.cn.
authors.forename: Ju
authors.initials: J
authors.lastname: Liu
authors.affiliation: Children's Health Care Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, Shandong 250014, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, China.
authors.forename: Fengyun
authors.initials: F
authors.lastname: Dong
authors.affiliation: Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Li
authors.affiliation: Molecular and Cellular Biology Division, Sunnybrook Health Science Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Molecular and Cellular Biology Division, Sunnybrook Health Science Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Thaddeus D
authors.initials: TD
authors.lastname: Allen
authors.affiliation: Molecular and Cellular Biology Division, Sunnybrook Health Science Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Miami Mice Research Corp., MaRS Centre, Heritage Bldg., 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Corrinne G
authors.initials: CG
authors.lastname: Lobe
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins / Q000235:genetics*; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D056970:Co-Repressor Proteins; D006877:Hydroxamic Acids; C434946:Tle1 protein, mouse; C012589:trichostatin A
keywords: ErbB1; ErbB2; Grg1; Lung adenocarcinoma; Transgenic mice; Trichostatin A