Histone demethylase RBP2 promotes lung tumorigenesis and cancer metastasis
Journal
Cancer Research
Journal Volume
73
Journal Issue
15
Pages
4711-4721
Date Issued
2013
Author(s)
Teng Y.-C.
Lee C.-F.
Li Y.-S.
Chen Y.-R.
Hsiao P.-W.
Chan M.-Y.
Lin F.-M.
Huang H.-D.
Chen Y.-T.
Hsu C.-H.
Yan Q.
Tsai M.-D.
Juan L.-J.
Abstract
The retinoblastoma binding protein RBP2 (KDM5A) is a histone demethylase that promotes gastric cancer cell growth and is enriched in drug-resistant lung cancer cells. In tumor-prone mice lacking the tumor suppressor gene RB or MEN1, genetic ablation of RBP2 can suppress tumor initiation, but the pathogenic breadth and mechanistic aspects of this effect relative to human tumors have not been defined. Here, we approached this question in the context of lung cancer. RBP2 was overexpressed in human lung cancer tissues where its depletion impaired cell proliferation, motility, migration, invasion, and metastasis. RBP2 oncogenicity relied on its demethylase and DNA-binding activities. RBP2 upregulated expression of cyclins D1 and E1 while suppressing the expression of cyclin-dependent kinase inhibitor p27 (CDKN1B), each contributing to RBP2-mediated cell proliferation. Expression microarray analyses revealed that RBP2 promoted expression of integrin-b1 (ITGB1), which is implicated in lung cancer metastasis. Mechanistic investigations established that RBP2 bound directly to the p27, cyclin D1, and ITGB1 promoters and that exogenous expression of cyclin D1, cyclin E1, or ITGB1 was sufficient to rescue proliferation or migration/invasion, respectively. Taken together, our results establish an oncogenic role for RBP2 in lung tumorigenesis and progression and uncover novel RBP2 targets mediating this role. ? 2013 American Association for Cancer Research.
SDGs
Other Subjects
beta1 integrin; cell antigen; cyclin D1; cyclin dependent kinase inhibitor 1B; cyclin E1; DNA; retinoblastoma binding protein 2; short hairpin RNA; unclassified drug; animal experiment; animal model; animal tissue; antineoplastic activity; article; cancer cell culture; carcinogenicity; cell invasion; cell migration; cell motility; cell proliferation; controlled study; female; gene silencing; human; human cell; human tissue; in vitro study; in vivo study; lung carcinogenesis; lung fibroblast; lung non small cell cancer; male; metastasis; mouse; nonhuman; priority journal; promoter region; protein depletion; protein DNA binding; protein expression; tumor promotion; Animals; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Chromatin Immunoprecipitation; Disease Progression; Female; Gene Knockdown Techniques; Humans; Lung Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Oligonucleotide Array Sequence Analysis; Retinol-Binding Proteins, Cellular; Reverse Transcriptase Polymerase Chain Reaction; Xenograft Model Antitumor Assays
Type
journal article