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Title: The role of glycine N-methyltransferase in the androgen-mediated development of prostate cancer
Author: Ottaviani, Silvia
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Prostate cancer is the most frequently diagnosed malignancy among men in the Western world. The development and growth of prostate cancer is dependent upon androgens, whose effects are mediated by the androgen receptor (AR), a member of the nuclear receptor superfamily of ligand-activated transcription factors. The identification of androgen-regulated genes in prostate cancer cells, particularly those involved in cell growth, cell survival and cell migration are, therefore, of great importance for defining the mechanisms of prostate cancer development and progression, and thus developing new markers and targets for prostate cancer treatment. Our laboratory has previously carried out gene expression microarray analysis using the androgen-responsive LNCaP prostate cancer cell line, to identify androgen-regulated genes. Amongst the most highly androgen-responsive genes was Glycine N-methyltransferase (GNMT). GNMT is a S-adenosylmethionine (SAM)-dependent methyltransferase which catalyses the transfer of the methyl group on SAM to the amino acid glycine to generate N-methyl glycine (sarcosine), a compound with poorly defined biological functions. Previous studies have suggested that GNMT may act as a tumour-susceptibility gene in prostate cancer, although the mechanisms by which GNMT acts in prostate cancer remain obscure. To ascertain the role of GNMT in prostate cancer, I have investigated GNMT expression and its regulation by AR. I show that GNMT expression is stimulated by androgen in AR-expressing cells and that the stimulation occurs at the mRNA and protein levels. I have identified an androgen-response element (ARE) within the first exon of the GNMT gene and demonstrated that AR binds to this element in vitro and in vivo. To investigate the role of GNMT in the androgen-mediated development of prostate cancer, I performed microarray analysis of LNCaP cells treated with two different GNMT small interference RNAs (siRNAs). I identified a cohort of genes that are differentially expressed upon GNMT knockdown, several of which have been implicated in cell cycle progression and motility. Finally, I have shown that GNMT over-expression impaired LNCaP cell migration in vitro, but did not affect LNCaP cell growth. Together, these studies identify GNMT as a direct transcriptional target of the AR and provide evidence for a role for GNMT in the androgen-mediated development and progression of prostate cancer.
Supervisor: Buluwela, Laki ; Ali, Simak Sponsor: Prostate Cancer Charitable Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available