Methylation and Inactivation of Estrogen, Progesterone, and Androgen Receptors in Prostate Cancer

Sasaki, Masahiro; Tanaka, Yuichiro; Perinchery, Geetha; Dharia, Abhipsa; Kotcherguina, Ioulia; Fujimoto, Sei ichiro; Dahiya, Rajvir

doi:10.1093/jnci/94.5.384

Cited by 178 publications

(134 citation statements)

References 22 publications

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“…Chromatin structure is also altered by histone acetylation, and histone H3 acetylation has been observed in the far upstream enhancer region and other CYP1B1 promoter elements through the interaction of histone acetyltransferase and CREB-binding protein (40). Additionally, promoter methylation of some CYP1B1 effectors and associated metabolic enzymes (including several steroid receptor genes and catechol-O-methyltransferase) have also been linked to differential gene expression in hormone-dependent cancers compared with normal tissue (44)(45)(46)(47)(48)(49). Thus, epigenetic regulation through methylation and acetylation of histones within the CYP1B1 promoter region is a key determinant of CYP1B1 transcription, and the degree of epigenetic regulation may be tissue specific, with those tissues relying on cAMP-mediated transcription of CYP1B1 most likely having a different chromatin structure than other tissues.…”

Section: Epigenetic Regulationmentioning

confidence: 99%

“…This suggests that CYP1B1-mediated metabolism could provide a protective effect against flutamide treatment in those tumors that express CYP1B1, and flutamide can cause the induction of CYP1B1 through indirect means. Furthermore, androgen-mediated tissues show an increased reliance on estrogen signaling during flutamide treatment (49,155). CYP1B1 induction could modulate this signaling and cause toxicity in flutamide-treated patients through the metabolism of estrogens and the formation of 4-OHE 2 .…”

Section: Androgen-mediated Cancersmentioning

confidence: 99%

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Pharmacogenetics and Regulation of Human CytochromeP450 1B1: Implications in Hormone-Mediated Tumor Metabolism and a Novel Target for Therapeutic Intervention

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Price

Sparreboom

et al. 2006

Molecular Cancer Research

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Several of the hormone-mediated cancers (breast, endometrial, ovarian, and prostate) represent major cancers in both incidence and mortality rates. The etiology of these cancers is in large part modulated by the hormones estrogen and testosterone. As advanced disease develops, the common treatment for these cancers is chemotherapy. Thus, genes that can alter tissue response to hormones and alter clinical response to chemotherapy are of major interest. The cytochrome P450 1B1 (CYP1B1) may be involved in disease progression and modulate the treatment in the above hormone-mediated cancers. This review will focus on the pharmacogenetics of CYP1B1 in relation to hormone-mediated cancers and provide an assessment of cancer risk based on CYP1B1 polymorphisms and expression. In addition, it will provide a summary of CYP1B1 gene regulation and expression in normal and neoplastic tissue. (Mol Cancer Res 2006;4(3):135 -50)

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Section: Epigenetic Regulationmentioning

confidence: 99%

Section: Androgen-mediated Cancersmentioning

confidence: 99%

Pharmacogenetics and Regulation of Human CytochromeP450 1B1: Implications in Hormone-Mediated Tumor Metabolism and a Novel Target for Therapeutic Intervention

Sissung

Price

Sparreboom

et al. 2006

Molecular Cancer Research

135

128

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“…In the second group, there were four tumor suppressor genes, including two cyclindependent kinase inhibitors: p27KIP1 [38]and p57KIP2 [39]; p53 analogue, p73 [38,40], as well as the Wilms tumor 1 gene, WT1. There were seven genes encoding the surface proteins or nuclear receptors acting actively in the intercellular interactions: galanin receptor 2 (GALR2) [42], melanoma specific antigen A1 (MAGEA1), the membrane metallo-endopeptidase (NEP) [43], solute carrier family 5 (NIS) [44], caveolin 1 (CAV) [45], chondroitin sulfate proteoglycan 2 (CSPG2) [46] and androgen receptor (AR) [47]. Three genes implicated in signal transduction, cyclin a1 [48], the interferon regulatory factor 7 (IRF7), and a serine/threonine kinase 11 (Peutz-Jeghers syndrome) gene (LKB1) [18] were selected.…”

Section: Methylation Profiling Of Twenty Four Genes With or Without Tmentioning

confidence: 99%

Methylation profiling of twenty four genes and the concordant methylation behaviours of nineteen genes that may contribute to hepatocellular carcinogenesis

Zhang

et al. 2003

Cell Res

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To determine the possible role of the epigenetic mechanisms in carcinogenesis of the hepatocellular carcinoma, we methylation-profiled the promoter CpG islands of twenty four genes both in HCC tumors and the neighboring non-cancerous tissues of twenty eight patients using the methylation-specific PCR (MSP) method in conjunction with the DNA sequencing. In comparison with the normal liver tissues from the healthy donors, it was found that while remained unmethylated the ABL, CAV, EPO, GATA3, LKB1, NEP, NFL, NIS and p27KIP1 genes, varying extents of the HCC specific hypermethylation were found associated with the ABO, AR, CSPG2, cyclin a1, DBCCR1, GALR2, IRF7, MGMT, MT1A, MYOD1, OCT6, p57 KIP2 , p73, WT1 genes, and demethylation with the MAGEA1 gene, respectively. Judged by whether the hypermethylated occurred in HCC more frequently than in their neighboring normal tissues, the hypermethylation status of the AR, DBCCR1, IRF7, OCT6, and p73 genes was considered as the event specific to the late stage, while that the rest that lacked such a distinguished contrast, as the event specific to the early stage of HCC carcinogenesis. Among all the clinical pathological parameters tested for the association with, the hypermethylation of the cyclin a1 gene was more prevalent in the non-cirrhosis group (P=0.021) while the hypermethylated p16INK4a gene was more common in the cirrhosis group (P=0.017). The concordant methylation behaviors of nineteen genes, including the four previously studied and their association with cirrhosis has been evaluated by the best subgroup selection method. The data presented in this report would enable us to shape our understanding of the mechanisms for the HCC specific loss of the epigenetic stability of the genome, as well as the strategy of developing the novel robust methylation based diagnostic and prognostic tools.

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“…It contains a typical CpG island within its promoter (5), and has been shown to be re-expressed in prostate cancer cell-lines treated with DNMT inhibitors such as 5-aza-2'deoxycytidine (6)(7)(8). Furthermore, methylation-specific PCR studies have shown that the promoter region of the ERβ gene is hypermethylated in prostate cancer tissue studies (6,8,9). The loss of ERβ in prostate cancer cell-lines and in tissue studies adds to an accumulating body of evidence supporting an antiproliferative role for ERβ in the prostate.…”

Section: Introductionmentioning

confidence: 99%

DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines

et al. 2007

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tom@pelhamcourt.clara.co.uk Introduction Epigenetic silencing mechanisms are increasingly thought to play a major role in the development of human cancers, including prostate cancer. The two major epigenetic regulatory mechanisms involve alterations in DNA methylation and histone acetylation status. Promoter CpG island hypermethylation and histone hypoacetylation, catalysed by DNA methyltransferase (DNMT) and histone deacetylase (HDAC) respectively, are associated with transcriptional repression. Evidence in other cancers suggests the two mechanisms are dynamically linked, yet few studies have examined the potential interaction of the two pathways in prostate cancer. Here we report a synergistic, apoptotic effect of treatment with a demethylating agent and a histone deacetylase inhibitor on cultured prostate cancer cells, with associated re-expression of the putative antiproliferative agent oestrogen receptor beta.Methods LNCaP, DU-145 and PC-3 cells were pre-treated with the DNMT inhibitor 5'-aza-2'-deoxycytidine (5-AZAC) for 72 hours followed by 24 hours combined treatment with 5-AZAC and the HDAC inhibitor trichostatin A (TSA). Following treatment, cells were either processed for cell proliferation, cell toxicity, cell viability and apoptosis assays, or harvested for quantitative real-time RT-PCR gene expression analyses. Assessed target genes were oestrogen receptor beta (ERβ), androgen receptor (AR), progesterone receptor (PGR) and prostate specific antigen (PSA). ResultsIn all cell-lines co-treatment with 5-AZAC and TSA was associated with significantly reduced cell proliferation when compared with control groups (p<0.05); associated reduced cell viability and increased cell death was seen in all cases. Caspase activation was significantly increased in the co-treatment group, indicating that apoptosis was a major mechanism of cell death. Most marked effects were seen in the androgen-dependent, AR-positive LNCaP cell-line. In all cell-lines a marked synergistic re-expression of ERβ was identified in the co-treatment group, a finding which was not seen for either AR or PSA. A similar re-expression of PGR was also identified. ConclusionsAt concentrations associated with gene re-expression, the DNA demethylating agent 5-AZAC and the HDAC inhibitor TSA co-operate in an additive and synergistic way to induce apoptosis in prostate cancer cell-lines. Increased apoptosis in the co-treatment group was associated with marked re-expression of ERβ, which is an intriguing finding, raising the possibility of further targeting of prostate cancer cells with ERβ-selective agents such as phytooestrogens and selective oestrogen receptor modulators (SERMs).

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Methylation and Inactivation of Estrogen, Progesterone, and Androgen Receptors in Prostate Cancer

Abstract: Certain steroid receptor genes appear to be inactivated by CpG methylation in prostate cancer tissue and cell lines.

Cited by 178 publications

References 22 publications

Pharmacogenetics and Regulation of Human CytochromeP450 1B1: Implications in Hormone-Mediated Tumor Metabolism and a Novel Target for Therapeutic Intervention

Pharmacogenetics and Regulation of Human CytochromeP450 1B1: Implications in Hormone-Mediated Tumor Metabolism and a Novel Target for Therapeutic Intervention

Methylation profiling of twenty four genes and the concordant methylation behaviours of nineteen genes that may contribute to hepatocellular carcinogenesis

DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines

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