Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable. Here we show, through gene expression profiling, that the polycomb group protein enhancer of zeste homolog 2 (EZH2) is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes targeted against EZH2 reduce the amounts of EZH2 protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.
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PMID:The polycomb group protein EZH2 is involved in progression of prostate cancer. 1237 61

Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. However, there are no reports of systemic delivery for siRNAs toward treatment of bone-metastatic cancer. Accordingly, we report here that i.v. injection of GL3 luciferase siRNA complexed with atelocollagen showed effective reduction of luciferase expression from bone-metastatic prostate tumor cells developed in mouse thorax, jaws, and/or legs. We also show that the siRNA/atelocollagen complex can be efficiently delivered to tumors 24 h after injection and can exist intact at least for 3 days. Furthermore, atelocollagen-mediated systemic administration of siRNAs such as enhancer of zeste homolog 2 and phosphoinositide 3'-hydroxykinase p110-alpha-subunit, which were selected as candidate targets for inhibition of bone metastasis, resulted in an efficient inhibition of metastatic tumor growth in bone tissues. In addition, upregulation of serum IL-12 and IFN-alpha levels was not associated with the in vivo administration of the siRNA/atelocollagen complex. Thus, for treatment of bone metastasis of prostate cancer, an atelocollagen-mediated systemic delivery method could be a reliable and safe approach to the achievement of maximal function of siRNA.
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PMID:Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo. 1609 73

Overexpression of the enhancer of zeste homolog 2 (EZH2) protein, a known repressor of gene transcription, has been reported to be associated with biological malignancy of prostate cancer and several other cancers. The purpose of this study was to examine the expression of EZH2 and analyze its relationship with the clinicopathological features of human gastric cancers. Expression levels of EZH2 mRNA and protein were examined in 13 gastric cancer cell lines and in 83 surgically removed human gastric cancer tissues. Immunohistochemical analysis of the 83 tissue samples and corresponding non-cancerous gastric mucosa showed that EZH2 was more highly expressed in the cancerous than in the non-cancerous tissues, and the expression levels of EZH2 were highly correlated with tumor size, depth of invasion, vessel invasion, lymph node metastasis and clinical stages. Univariate analysis of survival rate calculated by the Kaplan-Meier method revealed that gastric cancer patients with high-level EZH2 expression had poorer prognosis than those expressing no or low levels of EZH2 (P = 0.0271). These findings suggest that overexpression of EZH2 may contribute to the progression and oncogenesis of human gastric cancers, and thus immunohistochemical study of EZH2 expression may serve as a new biomarker for predicting the prognosis of gastric cancers.
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PMID:Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. 1673 26

PSP94, for prostatic secretory protein of 94 amino acids, is secreted by the prostate gland and functions as a suppressor of tumor growth and metastasis. The expression of PSP94 is lost in advanced, hormone-refractory prostate cancer and this correlates with an increased expression of the Polycomb protein EZH2 (enhancer of zeste homolog 2), which represses transcription via trimethylation of histone H3 on Lys27 (H3K27). We show here that these events are causally related and that the MSMB gene, which encodes PSP94, is trimethylated on H3K27 in androgen-refractory, but not in androgen-sensitive prostate cancer cells. Chromatin immunoprecipitation experiments confirmed an association of EZH2 with the MSMB gene. The RNAi-mediated knockdown of EZH2 resulted in a loss of H3K27 trimethylation and an increased expression of the MSMB gene. Conversely, the overexpression of EZH2 was associated with a decreased expression of the MSMB gene. We also demonstrate that MSMB is additionally repressed in androgen-refractory prostate cancer cells by the hypoacetylation of histone H3K9 and the hypermethylation of a CpG island in the promoter region. Our data disclose a hitherto unexplored link between the putative oncogene EZH2 and the tumor suppressor PSP94, and show that MSMB is silenced by EZH2 in advanced prostate cancer cells.
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PMID:The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2. 1723 10

The polycomb group protein enhancer of zeste homolog 2 (EZH2) is linked to aggressive prostate cancer and could be an appropriate target in specific immunotherapy. In this study, we attempted to identify EZH2-derived peptides that have the potential to generate cancer-reactive cytotoxic T lymphocytes (CTLs) in human leukocyte antigen (HLA)-A2+ prostate cancer patients. Twelve EZH2-derived peptides were prepared based on the HLA-A2 binding motif. These peptide candidates were screened first by their ability to be recognized by immunoglobulin G (IgG), and then by their ability to induce peptide-specific cytotoxic T lymphocytes (CTLs). As a result, five EZH2 peptides recognized by IgG (EZH2 120-128, EZH2 165-174, EZH2 569-577, EZH2 665-674, and EZH2 699-708) were frequently detected in the plasma of prostate cancer patients. Among them, the EZH2 120-128 and EZH2 165-174 peptides effectively induced HLA-A2-restricted and cancer-reactive CTLs from prostate cancer patients. The cytotoxicity was mainly dependent on EZH2 peptide-specific and HLA-A2-restricted CD8+ T cells. These results indicate that these EZH2 120-128 and EZH2 165-174 peptides could be promising candidates in peptide-based immunotherapy for HLA-A2+ prostate cancer patients.
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PMID:New peptides of the polycomb group protein enhancer of zeste homolog 2 with the potential to induce cancer-reactive cytotoxic T lymphocytes in human leukocyte antigen-A2+ prostate cancer patients. 1791 78

Androgens and the androgen receptor are important for both normal prostate development and progression of prostate cancer (PCa). However, the underlying mechanisms are not fully understood. The Polycomb protein enhancer of zeste homolog 2 (EZH2) functions as an epigenetic gene silencer and plays a role in oncogenesis by promoting cell proliferation and invasion. EZH2 has been implicated in human PCa progression, because its expression is often elevated in hormone-refractory PCa. Here, we demonstrated that expression of EZH2 is lower in androgen-sensitive LNCaP PCa cells compared with Rf and C4-2 cells, two androgen-refractory sublines that are derived from LNCaP cells. Androgen ablation by castration increased the level of EZH2 proteins in LNCaP xenografts in mice. In contrast, treatment of LNCaP cells in culture with the synthetic androgen methyltrieolone (R1881) at doses of 1 nm or higher suppressed EZH2 expression. Moreover, our data suggest that androgen repression of EZH2 requires a functional androgen receptor and this effect is mediated through the retinoblastoma protein and its related protein p130. We further showed that androgen treatment not only increases expression of EZH2 target genes DAB2IP and E-cadherin but also affects LNCaP cell migration. Our results reveal that androgens function as an epigenetic regulator in prostatic cells by repression of EZH2 expression through the retinoblastoma protein and p130-dependent pathways. Our findings also suggest that blockade of EZH2 derepression during androgen deprivation therapy may represent an effective tactic for the treatment of androgen-refractory PCa.
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PMID:Androgens suppress EZH2 expression via retinoblastoma (RB) and p130-dependent pathways: a potential mechanism of androgen-refractory progression of prostate cancer. 2088 Dec 51

Accumulating evidence shows that enhancer of zeste homolog 2 (E2H2) is upregulated in a broad range of cancer types, such as breast cancer, prostate cancer, ovarian cancer, and colon cancer. Therefore, inhibiting EZH2 expression may be a promising strategy for anticancer therapy. This review focuses on the current understanding of the mechanisms underlying EZH2 regulation that are involved in cancer progression. Also, it introduces two EZH2 inhibitors that target EZH2 and could be potentially applied in the treatment of cancer in the future.
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PMID:Update of research on the role of EZH2 in cancer progression. 2358 97

Many candidate biomarkers for diagnosis of prostate cancer have been investigated, but prostate-specific antigen (PSA) testing remains the frontline test for both mass screening and individual clinical testing. Although the PSA test is cost-effective, analytically reliable, and flexibly high throughput, it has a very weak correlation with prostate malignancy. This has resulted in over-diagnosis and over-treatment of patients leading to costly economic, social, and psychological impacts. PSA testing lacks the ability to molecularly characterize prostate diseases and define aggressiveness and lethality, which are necessary to influence choice of treatment. Therefore, newer molecular tests are beginning to replace the PSA tests. The prostate cancer antigen 3 test has shown superiority and is now widely used. The recently reported sarcosine urine test, the already delineated TMPRSS2: ETS fusion genes, the glutathione-S-transferase P1 serum marker, and enhancer of zeste homolog 2 biomarker may also help improve diagnosis and prognostication of prostate cancer. The analytical trend is toward a multiplex testing format using molecular and/or proteomic techniques that are reliable, accurate, reproducible, and ensure rapid quantitation. Therefore, validation of these newer biomarkers and their assays are necessary for both large-scale clinical trials and clinical utility.
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PMID:The end of the road for prostate specific antigen testing? 2397 30

Mechanisms underlying progression to androgen-independent prostate cancer following radical ablation therapy remain poorly defined. Although intraprostatic infections have been highlighted as potential cofactors, pathogen influences on pathways that support tumor regrowth are not known. To explore this provocative concept, we derived androgen-sensitive and -insensitive prostate epithelial cells persistently infected with human herpesvirus 8 (HHV-8), an oncogenic herpesvirus that has been detected in normal prostate epithelium, prostate adenocarcinoma, and biologic fluids of patients with prostate cancer, to explore its effects on transition to hormone-refractory disease. Strikingly, we found that HHV-8 infection of androgen-sensitive prostate cancer cells conferred the capacity for androgen-independent growth. This effect was associated with altered expression and transcriptional activity of the androgen receptor (AR). However, HHV-8 infection bypassed AR signaling by promoting enhancer of zeste homolog 2 (EZH2)-mediated epigenetic silencing of tumor-suppressor genes, including MSMB and DAB2IP that are often inactivated in advanced disease. Furthermore, we found that HHV-8 triggered epithelial-to-mesenchymal transition. Although HHV-8 has not been linked etiologically to prostate cancer, virologic outcomes revealed by our study provide mechanistic insight into how intraprostatic infections could constitute risk for progression to androgen-independent metastatic disease where EZH2 has been implicated. Taken together, our findings prompt further evaluations of the relationship between HHV-8 infections and risk of advanced prostate cancer.
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PMID:Oncogenic herpesvirus HHV-8 promotes androgen-independent prostate cancer growth. 2400 34

The histone methyltransferase EZH2 (enhancer of zeste homolog 2) plays critical roles in prostate cancer (PCa) development and is a potential target for PCa treatment. Triptolide possesses anti-tumor activity, but it is unknown whether its therapeutic effect relates with EZH2 in PCa. Here we described EZH2 as a target for Triptolide in PCa cells. Our data showed that Triptolide suppressed PCa cell growth and reduced the expression of EZH2. Overexpression of EZH2 attenuated the Triptolide induced cell growth inhibition. Moreover, Triptolide treatment of PC-3 cells resulted in elevated mRNA levels of target genes (ADRB2, CDH1, CDKN2A and DAB2IP) negatively regulated by EZH2 as well as reduced mRNA levelsan of EZH2 positively regulated gene (cyclin D1). Our findings suggest the PCa cell growth inhibition mediated by Triptolide might be associated with downregulation of EZH2 expression and the subsequent modulation of target genes.
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PMID:Triptolide inhibits histone methyltransferase EZH2 and modulates the expression of its target genes in prostate cancer cells. 2428 59


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