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Expression of the IL‐11 Gene in Metastatic Cells Is Supported by Runx2‐Smad and Runx2‐cJun Complexes Induced by TGFβ1
Author(s) -
Zhang Xuhui,
Wu Hai,
Dobson Jason R.,
Browne Gillian,
Hong Deli,
Akech Jacqueline,
Languino Lucia R.,
Stein Gary S.,
Lian Jane B.
Publication year - 2015
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25167
Subject(s) - smad , runx2 , gene knockdown , transcription factor , cancer research , biology , signal transduction , microbiology and biotechnology , chemistry , cell culture , gene , genetics
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. J. Cell. Biochem. 116: 2098–2108, 2015. © 2015 Wiley Periodicals, Inc.