The biological action of androgenic male sex steroid hormones in prostate tissue is mediated by the androgen receptor, a nuclear transcription factor. The transcriptional program of androgenic signaling in the prostate consists of thousands of gene targets whose products play a role in almost all cellular functions, including cellular proliferation, survival, lipid metabolism, and differentiation. This review will provide a summary of the most recent data regarding androgen-regulated target genes and modulation of androgen receptor activity, especially with regard to androgen-dependent and castration-recurrent prostate cancer.
"Ligand-bound AR binds to specific androgen response elements (AREs) and induces transcription of target genes . In addition, there is evidence that AR may also induce or inhibit transcription of particular target genes by interacting with coregulator proteins, termed coactivators or corepressors . AR is expressed in many types of normal and malignant cells, regardless of sex    . "
[Show abstract][Hide abstract] ABSTRACT: Recently, deleted in breast cancer 1 (DBC1) has been suggested as a poor prognostic indicator of various human cancers and may possibly have a role as a coactivator of androgen receptor (AR). However, their roles in lymphoma are still unknown.
We investigated the effect of the expression of DBC1 and AR in diffuse large B cell lymphoma (DLBCL). Immunohistochemical expression of DBC1 and AR were evaluated in 101 DLBCL samples by tissue microarray.
Positive expression of DBC1 and AR was seen in 73% and 70% of DLBCL, respectively. In total DLBCL patients, DBC1 and AR expression were significantly associated with high clinical stage, elevated serum lactate dehydrogenase levels, and high international prognostic index scores, and they predicted shorter overall survival (OS) and relapse-free survival (RFS) by univariate analysis. DBC1 expression was also an independent prognostic indicator by multivariate analysis (OS, P = .017; RFS, P = .004). Especially, both DBC1 and AR expression significantly correlated with shorter OS and RFS in non-germinal center B cell (non-GCB)-type DLBCL by univariate analysis. In multivariate analysis, DBC1 expression was an independent prognostic predictor for OS (P = .035) and AR expression significantly correlated with RFS (P = .005).
We demonstrate that the expression of DBC1 and AR are significant prognostic indicators for DLBCL patients, especially for unfavorable non-GCB-type DLBCL.
"Androgen receptor, AR, turnover has been previously shown to be critical for the proliferation of prostate cancer cells , , . PIM1 kinase may regulate AR stability and translational activity in a phosphorylation-dependent manner . "
[Show abstract][Hide abstract] ABSTRACT: The Pim proteins are a family of highly homologous protein serine/threonine kinases that have been found to be overexpressed in cancer. Elevated levels of Pim1 kinase were first discovered in human leukemia and lymphomas. However, more recently Pim1 was found to be increased in solid tumors, including pancreatic and prostate cancers, and has been proposed as a prognostic marker. Although the Pim kinases have been identified as oncogenes in transgenic models, they have weak transforming abilities on their own. However, they have been shown to greatly enhance the ability of other genes or chemical carcinogens to induce tumors. To explore the role of Pim1 in prostate cancer, we generated conditional Pim1 transgenic mice, expressed Pim1 in prostate epithelium, and analyzed the contribution of PIM1 to neoplastic initiation and progression. Accordingly, we explored the effect of PIM1 overexpression in 3 different settings: upon hormone treatment, during aging, and in combination with the absence of one Pten allele. We have found that Pim1 overexpression increased the severity of mouse prostate intraepithelial neoplasias (mPIN) moderately in all three settings. Furthermore, Pim1 overexpression, in combination with the hormone treatment, increased inflammation surrounding target tissues leading to pyelonephritis in transgenic animals. Analysis of senescence induced in these prostatic lesions showed that the lesions induced in the presence of inflammation exhibited different behavior than those induced in the absence of inflammation. While high grade prostate preneoplastic lesions, mPIN grades III and IV, in the presence of inflammation did not show any senescence markers and demonstrated high levels of Ki67 staining, untreated animals without inflammation showed senescence markers and had low levels of Ki67 staining in similar high grade lesions. Our data suggest that Pim1 might contribute to progression rather than initiation in prostate neoplasia.
PLoS ONE 05/2013; 8(4):e60277. DOI:10.1371/journal.pone.0060277 · 3.23 Impact Factor
"The androgen receptor (AR) is a member of the nuclear receptor superfamily that regulates ligand-dependent gene transcription
. Upon androgen binding, AR translocates to the nucleus and binds to consensus sequences of androgen response elements (AREs) in the genome to activate genes, such as prostate-specific antigen (PSA)
[2,3]. Many of these AR-regulated genes are key regulators of prostate development and maintenance. "
[Show abstract][Hide abstract] ABSTRACT: Background
Androgen receptor (AR) signalling is critical to the initiation and progression of prostate cancer (PCa). Transcriptional activity of AR involves chromatin recruitment of co-activators, including the p300/CBP-associated factor (PCAF). Distinct miRNA expression profiles have been identified in PCa cells during the development and progression of the disease. Whether miRNAs regulate PCAF expression in PCa cells to regulate AR transcriptional activity is still unclear.
Expression of PCAF was investigated in several PCa cell lines by qRT-PCR, Western blot, and immunocytochemistry. The effects of PCAF expression on AR-regulated transcriptional activity and cell growth in PCa cells were determined by chromatin immunoprecipitation, reporter gene construct analysis, and MTS assay. Targeting of PCAF by miR-17-5p was evaluated using the luciferase reporter assay.
PCAF was upregulated in several PCa cell lines. Upregulation of PCAF promoted AR transcriptional activation and cell growth in cultured PCa cells. Expression of PCAF in PCa cells was associated with the downregulation of miR-17-5p. Targeting of the 3’-untranslated region of PCAF mRNA by miR-17-5p caused translational suppression and RNA degradation, and, consequently, modulation of AR transcriptional activity in PCa cells.
PCAF is upregulated in cultured PCa cells, and upregulation of PCAF is associated with the downregulation of miR-17-5p. Targeting of PCAF by miR-17-5p modulates AR transcriptional activity and cell growth in cultured PCa cells.
BMC Cancer 10/2012; 12(1):492. DOI:10.1186/1471-2407-12-492 · 3.36 Impact Factor
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