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.

Lutein attenuates angiotensin II- induced cardiac remodeling by inhibiting AP-1/IL-11 signaling

“…Activator protein 1 (AP-1) is a transcription factor complex composed of members of the Fos and Jun families that has been reported to transactivate the IL-11 gene [ [32] , [33] , [34] ]. Therefore, we hypothesized that the protective effect of lutein on Ang II-induced cardiac remodeling was associated with AP-1 complex activity.…”

Identification of sequence-specific interactions of the CD44-intracellular domain with RUNX2 in the transcription of matrix metalloprotease-9 in human prostate cancer cells

“…We also previously identified a functional association between RUNX2 and CD44-ICD in PC3 cells in which CD44-ICD localization was increased in the nucleus of PC3 cells overexpressing RUNX2 [22] . RUNX2, a transcription factor, plays multiple roles in cancer progression [23][24][25] . RUNX2 regulates the transcription of genes such as MMP2 and MMP-9.…”

A microRNA/Runx1/Runx2 network regulates prostate tumor progression from onset to adenocarcinoma in TRAMP mice

“…Abnormally high levels of Runx2, and their targeted genes, in human prostate tissue and cells lines positively correlate with tumor stage and aggressiveness [ 19 , 21 ]. Our previous studies, and those of other laboratories, have documented the osteomimetic properties of Runx2 in primary tumors and that inhibition of Runx2 in breast and prostate cancer cells blocks metastasis and osteolytic bone disease mediated by human tumor cells in orthotopic mouse models [ 19 , 21 – 23 ].…”