Induction of Krüppel-Like Factor 5 Expression by Androgens Results in Increased CXCR4-Dependent Migration of Prostate Cancer Cells<i>in Vitro</i>

Frigo, Daniel E.; Sherk, Andrea B.; Wittmann, Bryan M.; Norris, John D.; Wang, Qianben; Joseph, James D.; Toner, Aidan; Brown, Myles; McDonnell, Donald P.

doi:10.1210/me.2009-0010

Cited by 65 publications

(91 citation statements)

References 57 publications

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“…Moreover, cycloheximide did not affect DHT-mediated induction of KLF5 mRNA level, suggesting that KLF5 was a primary responsive gene of androgen. In consistent with our present results Frigo et al (2009), previously reported a direct induction of KLF5 mRNA expression by R1881, synthetic androgen, in a prostate cancer cell line (LNCaP). They also identified putative ARE in first intron of KLF5 gene.…”

Section: K Takagi Et Al: Klf5 In Breast Carcinomasupporting

confidence: 94%

“…pKLF5-ARE-Luc and pPSAE-Luc plasmids). At first, pKLF5-ARE-Luc plasmids were constructed to examine possible recruitment of AR into putative androgen-responsive element(s) (ARE) in first intron of KLF5 gene identified by Frigo et al (2009). Briefly, 158 bp DNA region containing ARE within was amplified by PCR method using adapter primers (forward 5 0 -TAGGTACCTCAGTGGATACAAGGTTTTGC-3 0 and reverse 5 0 -TATAAGCTTCGATGCAAACCTT-TAAAATATTGC-3 0 ).…”

Section: Luciferase Assaymentioning

confidence: 99%

“…We next performed luciferase assay to examine possible recruitment of AR into ARE of KLF5 gene previously identified by Frigo et al (2009) using pKLF5-ARE-Luc plasmids. The luciferase activity was not significantly increased by DHT (0.99-fold, PZ0.93) in MCF-7 cells, although it was 1.2-fold (PZ0.04) increased in T-47D cells (Fig.…”

Section: Endocrine-related Cancermentioning

confidence: 99%

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Krüppel-like factor 5 in human breast carcinoma: a potent prognostic factor induced by androgens

Takagi¹,

Miki²,

Onodera³

et al. 2012

Endocrine-Related Cancer

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Krü ppel-like factor 5 (intestinal) or Krü ppel-like factor 5 (KLF5) is a zinc finger-containing transcription factor and involved in important biological processes including cell proliferation and differentiation. However, clinical significance of KLF5 protein has remained largely unknown in breast cancer. Therefore, in this study, we immunolocalized KLF5 in 113 human breast carcinoma cases. KLF5 immunoreactivity was frequently detected in the nuclei of breast carcinoma cells, and median value of the ratio of KLF5-positive carcinoma cells was 30% and was positively associated with the status of androgen receptor. KLF5 immunoreactivity was also significantly associated with increased risk of recurrence and worse clinical outcome in breast cancer patients by univariate analyses, and subsequent multivariate analyses demonstrated that KLF5 immunoreactivity was an independent prognostic factor for both disease-free and breast cancer-specific survival of the patients. We then examined possible regulation of KLF5 by androgen using MCF-7 breast carcinoma cells. KLF5 mRNA was induced by biologically active androgen 5a-dihydrotestosterone in a dose-and time-dependent manner in MCF-7 cells. In addition, results of transfection experiments demonstrated that proliferation activity of MCF-7 cells was significantly associated with the KLF5 expression level. These findings suggest that KLF5 is an androgen-responsive gene in human breast carcinomas and play important roles in the progression of breast carcinomas. KLF5 immunoreactivity is therefore considered a potent prognostic factor in human breast cancers.

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Section: K Takagi Et Al: Klf5 In Breast Carcinomasupporting

confidence: 94%

Section: Luciferase Assaymentioning

confidence: 99%

Section: Endocrine-related Cancermentioning

confidence: 99%

See 1 more Smart Citation

Krüppel-like factor 5 in human breast carcinoma: a potent prognostic factor induced by androgens

Takagi¹,

Miki²,

Onodera³

et al. 2012

Endocrine-Related Cancer

View full text Add to dashboard Cite

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“…Strikingly, however, a number of the top 20 genes uniquely regulated by cyclin D1b are functionally associated with altered cell migration, invasion, or differentiation, including NTN4, CXCR4, and SNAI2 (Table 1). Of these genes, only CXCR4 and SNAI2 have been shown to be regulated by androgens (16,26). Moreover, comparison of the cyclin D1b-specific gene set (cluster 3) with a recently identified metastasis-associated gene signature across multiple cancer types uncovered commonalities between the 2 gene sets (Supplemental Figure 1D), with SNAI2 as the top cyclin D1b-regulated gene present in this signature (whereas no overlap was seen with the cyclin D1a, cluster 2, gene set).…”

Section: Cyclin D1b Induces a Unique Gene Expression Program Associatmentioning

confidence: 99%

“…Recent findings implicating AR in the regulation of processes associated with metastasis heightened the importance of assessing Slug function in the context of ARpositive tumor cells (26). It is important to note that while the vast majority of metastatic human PCa retains AR, none of the AR-positive model systems reliably spontaneously metastasize in immunocompromised mice (44,45).…”

Section: Slug Enhances Prometastatic Phenotypes Of Pca Cells In Vivomentioning

confidence: 99%

Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes

Augello¹,

Burd²,

Birbe³

et al. 2012

J. Clin. Invest.

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Cyclin D1b is a splice variant of the cell cycle regulator cyclin D1 and is known to harbor divergent and highly oncogenic functions in human cancer. While cyclin D1b is induced during disease progression in many cancer types, the mechanisms underlying cyclin D1b function remain poorly understood. Herein, cell and human tumor xenograft models of prostate cancer were utilized to resolve the downstream pathways that are required for the protumorigenic functions of cyclin D1b. Specifically, cyclin D1b was found to modulate the expression of a large transcriptional network that cooperates with androgen receptor (AR) signaling to enhance tumor cell growth and invasive potential. Notably, cyclin D1b promoted AR-dependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of SNAI2 (Slug) was essential for cyclin D1b-mediated proliferative and invasive properties, implicating Slug as a critical driver of disease progression. Importantly, cyclin D1b expression highly correlated with that of Slug in clinical samples of advanced disease. In vivo analyses provided strong evidence that Slug enhances both tumor growth and metastatic phenotypes. Collectively, these findings reveal the underpinning mechanisms behind the protumorigenic functions of cyclin D1b and demonstrate that the convergence of the cyclin D1b/AR and Slug pathways results in the activation of processes critical for the promotion of lethal tumor phenotypes.

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The miRNAs 203a/210‐3p/5001‐5p regulate the androgen/androgen receptor/YAP‐induced migration in prostate cancer cells

Huo,

Kuo,

Lin

et al. 2024

Cancer Medicine

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BackgroundProstate cancer (PCa) patients with elevated level of androgen receptor (AR) correlate with higher metastatic incidence. Protein expression of AR and its target gene prostate‐specific antigen (PSA) are elevated in metastatic prostate tumors as compared to organ‐confined tumors. Androgen treatment or elevation of AR promotes metastasis of PCa in cell culture and murine model. However, under androgen depleted condition, AR suppressed cell mobility and invasiveness of PCa cells. Androgen deprivation therapy in PCa patients is associated with higher risk of cancer metastasis. We therefore investigated the dual roles of AR and miRNAs on PCa metastasis.MethodsThe PC‐3AR (PC‐3 cells re‐expressing AR) and LNCaP cells were used as PCa cell model. Transwell migration and invasion assay, wound‐healing assay, zebrafish xenotransplantation assay, and zebrafish vascular exit assay were used to investigate the role of AR and androgen on PCa metastasis. Micro‐Western Array, co‐immunoprecipitation and Immunofluorescence were applied to dissect the molecular mechanism lying underneath. The miRNA array, miRNA inhibitors or plasmid, and chromatin immunoprecipitation assay were used to study the role of miRNAs on PCa metastasis.ResultsIn the absence of androgen, AR repressed the migration and invasion of PCa cells. When androgen was present, AR stimulated the migration and invasion of PCa cells both in vitro and in zebrafish xenotransplantation model. Androgen increased phospho‐AR Ser81 and yes‐associated protein 1 (YAP), decreased phospho‐YAP Ser217, and altered epithelial‐mesenchymal transition (EMT) proteins in PCa cells. Co‐IP assay demonstrated that androgen augmented the interaction between YAP and AR in nucleus. Knockdown of YAP or treatment with YAP inhibitor abolished the androgen‐induced migration and invasion of PCa cells, while overexpression of YAP showed opposite effects. The miRNA array revealed that androgen decreased hsa‐miR‐5001‐5p but increased hsa‐miR‐203a and hsa‐miR‐210‐3p in PC‐3AR cells but not PC‐3 cells. Treatment with inhibitors targeting hsa‐miR‐203a/hsa‐miR‐210‐3p, or overexpression of hsa‐miR‐5001‐5p decreased YAP expression as well as suppressed the androgen‐induced migration and invasion of PCa cells. Chromatin immunoprecipitation (ChIP) assay demonstrated that AR binds with promoter region of has‐miR‐210‐3p in the presence of androgen.ConclusionsOur observations indicated that miRNAs 203a/210‐3p/5001‐5p regulate the androgen/AR/YAP‐induced PCa metastasis.

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Induction of Krüppel-Like Factor 5 Expression by Androgens Results in Increased CXCR4-Dependent Migration of Prostate Cancer Cellsin Vitro

Cited by 65 publications

References 57 publications

Krüppel-like factor 5 in human breast carcinoma: a potent prognostic factor induced by androgens

Krüppel-like factor 5 in human breast carcinoma: a potent prognostic factor induced by androgens

Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes

The miRNAs 203a/210‐3p/5001‐5p regulate the androgen/androgen receptor/YAP‐induced migration in prostate cancer cells

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