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FOXO1 inhibits Runx2 transcriptional activity and prostate cancer cell migration and invasion.

ABSTRACT: Prostate cancer patients with regional lymph node involvement at radical prostatectomy often experience disease progression to other organs, with the bone as the predominant site. The transcription factor Runx2 plays an important role in bone formation and prostate cancer cell migration, invasion, and metastasis. Here we showed that the forkhead box O (FOXO1) protein, a key downstream effector of the tumor suppressor PTEN, inhibits the transcriptional activity of Runx2 in prostate cancer cells. This inhibition was enhanced by PTEN but diminished by active Akt. FOXO1 bound to Runx2 in vitro and in vivo and suppressed Runx2's activity independent of its transcriptional function. FOXO1 inhibited Runx2-promoted migration of prostate cancer cells, whereas silencing of endogenous FOXO1 enhanced prostate cancer cell migration in a Runx2-dependent manner. Forced expression of FOXO1 also inhibited Runx2-promoted prostate cancer cell invasion. Finally, we found that expression of PTEN and the level of FOXO1 in the nucleus is inversely correlated with expression of Runx2 in a cohort of prostate cancer specimens from patients with lymph node and bone metastasis. These data reveal FOXO1 as a critical negative regulator of Runx2 in prostate cancer cells. Inactivation of FOXO1 due to frequent loss of PTEN in prostate cancer cells may leave the oncogenic activities of Runx2 unchecked, thereby driving promiscuous expression of Runx2 target genes involved in cell migration and invasion and favoring prostate cancer progression.

SUBMITTER: Zhang H

PROVIDER: S-EPMC3108023 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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FOXO1 inhibits Runx2 transcriptional activity and prostate cancer cell migration and invasion.

Zhang Haijun H Pan Yunqian Y Zheng Li L Choe Chungyoul C Lindgren Bruce B Jensen Eric D ED Westendorf Jennifer J JJ Cheng Liang L Huang Haojie H

Cancer research 20110419 9

Prostate cancer patients with regional lymph node involvement at radical prostatectomy often experience disease progression to other organs, with the bone as the predominant site. The transcription factor Runx2 plays an important role in bone formation and prostate cancer cell migration, invasion, and metastasis. Here we showed that the forkhead box O (FOXO1) protein, a key downstream effector of the tumor suppressor PTEN, inhibits the transcriptional activity of Runx2 in prostate cancer cells. ...[more]

PMID: 21505104

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Project description:BackgroundG protein-coupled bile acid receptor 1 (GPBAR1) is a G protein-coupled receptor for bile acids, which is widely expressed in many human tissues. Patchouli alcohol (PA) has been shown to have an anti-cancer effect, including in prostate cancer (PCa). This study sought to confirm the regulatory mechanism of GPBAR1 in the anti-cancer activity of PA in PCa.MethodsThe SwissTargetPrediction website (Pro >0) was used to predict the target of PA. The UALCAN and The Cancer Genome Atlas-Prostate cohort was used to examine the differentially expressed genes and PCa recurrence. A gene set enrichment analysis (GSEA) was conducted to analyze the relationship between the expression of GPBAR1 and PCa proliferation, migration, and invasion. Cell proliferation, migration, and invasion were assessed by colony formation, 5-Ethynyl-2'-deoxyuridine staining, cell scratch assays, and Transwell invasion assays, respectively. A xenograft animal model was established to assess the effect of PA on tumor growth in vivo. GPBAR1 protein and apoptosis related protein expression was measured by western blot.ResultsGPBAR1 was a PA target predicted by the SwissTargetPrediction website. PA inhibited the expression of GPBAR1 in PCa cells in a time- and dose-dependent manner. The abnormal expression of GPBAR1 was related to cell proliferation, migration, and invasion. Additionally, GPBAR1 overexpression promoted the cell proliferation, migration, and invasion, and inhibited the apoptosis of PCa cells. GPBAR1 silencing inhibited the cell proliferation, migration, and invasion, and promoted the apoptosis of PCa cells. High expressions of GPBAR1 suppressed tumor growth in tumor-bearing mice. Further, GPBAR1 promoted the activation of nuclear factor kappa B (NF-κB) signaling, and PA regulated the malignant phenotypes of PCa cells via the NF-κB signaling pathway mediated by GPBAR1.ConclusionsGPBAR1 is a promising drug target of PA, and was shown to regulate the proliferation, apoptosis, migration, and invasion of PCa cells through GPBAR1/NF-κB inhibition.

Project description:Previously, we have identified the RUNX2 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from epithelial ovarian cancer (EOC) patients, when compared to primary cultures derived from matched primary (prior to CT) tumors. However, we found no differences in the RUNX2 methylation in primary EOC tumors and EOC omental metastases, suggesting that DNA methylation-based epigenetic mechanisms have no impact on RUNX2 expression in advanced (metastatic) stage of the disease. Moreover, RUNX2 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. Knockdown of the RUNX2 expression in EOC cells led to sharp decrease of cell proliferation and significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as various genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX2 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX2 gene in EOC progression and suggest that RUNX2 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX2 and other members of the RUNX gene family in ovarian tumorigenesis. To better understand the molecular mechanisms of RUNX2 gene action in ovarian cancer cells, we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon RUNX2 suppression in SKOV3 cells. We compared the gene expression of the previously selected clone shRNA- RUNX2-knockdown clone 3 (cl3) against the corresponding control clone. The microarray experiments were performed in duplicates, as two hybridizations were carried out for the RUNX2-suppressing cell clone against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.

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FOXO1 inhibits Runx2 transcriptional activity and prostate cancer cell migration and invasion.

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FOXO1 inhibits Runx2 transcriptional activity and prostate cancer cell migration and invasion.

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