title: Expression of the IL-11 Gene in Metastatic Cells Is Supported by Runx2-Smad and Runx2-cJun Complexes Induced by TGFβ1.
abstract: In tumor cells, two factors are abnormally increased that contribute to metastatic bone disease: Runx2, a transcription factor that promotes expression of metastasis related and osteolytic genes; and IL-11, a secreted osteolytic cytokine. Here, we addressed a compelling question: Does Runx2 regulate IL-11 gene expression? We find a positive correlation between Runx2, IL-11 and TGFβ1, a driver of the vicious cycle of metastatic bone disease, in prostate cancer (PC) cell lines representing early (LNCaP) and late (PC3) stage disease. Further, like Runx2 knockdown, IL-11 knockdown significantly reduced expression of several osteolytic factors. Modulation of Runx2 expression results in corresponding changes in IL-11 expression. The IL-11 gene has Runx2, AP-1 sites and Smad binding elements located on the IL-11 promoter. Here, we demonstrated that Runx2-c-Jun as well as Runx2-Smad complexes upregulate IL-11 expression. Functional studies identified a significant loss of IL-11 expression in PC3 cells in the presence of the Runx2-HTY mutant protein, a mutation that disrupts Runx2-Smad signaling. In response to TGFβ1 and in the presence of Runx2, we observed a 30-fold induction of IL-11 expression, accompanied by increased c-Jun binding to the IL-11 promoter. Immunoprecipitation and in situ co-localization studies demonstrated that Runx2 and c-Jun form nuclear complexes in PC3 cells. Thus, TGFβ1 signaling induces two independent transcriptional pathways - AP-1 and Runx2. These transcriptional activators converge on IL-11 as a result of Runx2-Smad and Runx2-c-Jun interactions to amplify IL-11 gene expression that, together with Runx2, supports the osteolytic pathology of cancer induced bone disease.
authors: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine Burlington, Vermont, USA.|Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Xuhui
authors: X
authors: Zhang
authors: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine Burlington, Vermont, USA.
authors: Hai
authors: H
authors: Wu
authors: Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Jason R
authors: JR
authors: Dobson
authors: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine Burlington, Vermont, USA.
authors: Gillian
authors: G
authors: Browne
authors: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine Burlington, Vermont, USA.
authors: Deli
authors: D
authors: Hong
authors: Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Jacqueline
authors: J
authors: Akech
authors: Prostate Cancer Discovery and Development Program and Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors: Lucia R
authors: LR
authors: Languino
authors: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine Burlington, Vermont, USA.
authors: Gary S
authors: GS
authors: Stein
authors: Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine Burlington, Vermont, USA.
authors: Jane B
authors: JB
authors: Lian
mesh_terms: D001665:Binding Sites; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D017370:Interleukin-11 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D046912:Multiprotein Complexes / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C508611:IL11 protein, human; D017370:Interleukin-11; D046912:Multiprotein Complexes; D016755:Proto-Oncogene Proteins c-jun; C493709:RUNX2 protein, human; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1
keywords: BONE METASTASIS; IL-11 GENE; PROSTATE CANCER; Runx2