Runx2 transcriptome of prostate cancer cells: insights into invasiveness and bone metastasis

Abstract

BackgroundProstate cancer (PCa) cells preferentially metastasize to bone at least in part by acquiring osteomimetic properties. Runx2, an osteoblast master transcription factor, is aberrantly expressed in PCa cells, and promotes their metastatic phenotype. The transcriptional programs regulated by Runx2 have been extensively studied during osteoblastogenesis, where it activates or represses target genes in a context-dependent manner. However, little is known about the gene regulatory networks influenced by Runx2 in PCa cells. We therefore investigated genome wide mRNA expression changes in PCa cells in response to Runx2.ResultsWe engineered a C4-2B PCa sub-line called C4-2B/Rx2dox, in which Doxycycline (Dox) treatment stimulates Runx2 expression from very low to levels observed in other PCa cells. Transcriptome profiling using whole genome expression array followed by in silico analysis indicated that Runx2 upregulated a multitude of genes with prominent cancer associated functions. They included secreted factors (CSF2, SDF-1), proteolytic enzymes (MMP9, CST7), cytoskeleton modulators (SDC2, Twinfilin, SH3PXD2A), intracellular signaling molecules (DUSP1, SPHK1, RASD1) and transcription factors (Sox9, SNAI2, SMAD3) functioning in epithelium to mesenchyme transition (EMT), tissue invasion, as well as homing and attachment to bone. Consistent with the gene expression data, induction of Runx2 in C4-2B cells enhanced their invasiveness. It also promoted cellular quiescence by blocking the G1/S phase transition during cell cycle progression. Furthermore, the cell cycle block was reversed as Runx2 levels declined after Dox withdrawal.ConclusionsThe effects of Runx2 in C4-2B/Rx2dox cells, as well as similar observations made by employing LNCaP, 22RV1 and PC3 cells, highlight multiple mechanisms by which Runx2 promotes the metastatic phenotype of PCa cells, including tissue invasion, homing to bone and induction of high bone turnover. Runx2 is therefore an attractive target for the development of novel diagnostic, prognostic and therapeutic approaches to PCa management. Targeting Runx2 may prove more effective than focusing on its individual downstream genes and pathways.

Lung Tumor-associated Osteoblast-derived Bone Morphogenetic Protein-2 Increased Epithelial-to-Mesenchymal Transition of Cancer by Runx2/Snail Signaling Pathway

“…In addition, stimulating bone remodeling gives tumor cells more possibilities to successfully colonize this environment and support further tumor growth (29). Runx2, a pivotal factor in the progression of osteogenesis, has been found to be up-regulated in various types of malignancies that are metastatic to bone (33). Also, overexpression of Runx2 in cancer cells increases the expression of bone matrix and adhesion proteins, matrix metalloproteinases, and pro-angiogenic factors, which are strongly associated with cancer metastasis (34,35).…”

Prolyl Isomerase Pin1-mediated Conformational Change and Subnuclear Focal Accumulation of Runx2 Are Crucial for Fibroblast Growth Factor 2 (FGF2)-induced Osteoblast Differentiation

“…2B). A protein life span analysis using tetracycline-inducible Runx2 expression system (38) demonstrated that Runx2 stability is strongly decreased by Pin1 deficiency (Fig. 2C), indicating that Pin1 is still functioning in FGFR2-enhanced Runx2 protein stabilization.…”

Regulation of Breast Cancer-induced Bone Lesions by β-Catenin Protein Signaling

“…In prostate cancer bone metastasis, tumor cells can produce high level Runx-2, which promote tissue invasion, homing to bone, as well as osteoblastic differentiation (39). Furthermore, Barnes et al reported that human breast cancer cells can produce Runx-2, which activates bone sialoprotein and contributes to an osteoblastic phenotype in bone metastasis (40).…”