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Androgen-regulated genes differentially modulated by the androgen receptor coactivator L-dopa decarboxylase in human prostate cancer cells.

Margiotti K, Wafa LA, Cheng H, Novelli G, Nelson CC, Rennie PS - Mol. Cancer (2007)

Bottom Line: There were a total of 35 differentially expressed genes, 25 up-regulated and 10 down-regulated, in the DDC overexpressing cell line.In particular, we found a well-known androgen induced gene, TMEPAI, which wasup-regulated in DDC overexpressing cells, supporting its known co-activation function.In addition, DDC also further augmented the transcriptional repression function of AR for a subset of androgen-repressed genes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. katia.margiotti@vch.ca

ABSTRACT

Background: The androgen receptor is a ligand-induced transcriptional factor, which plays an important role in normal development of the prostate as well as in the progression of prostate cancer to a hormone refractory state. We previously reported the identification of a novel AR coactivator protein, L-dopa decarboxylase (DDC), which can act at the cytoplasmic level to enhance AR activity. We have also shown that DDC is a neuroendocrine (NE) marker of prostate cancer and that its expression is increased after hormone-ablation therapy and progression to androgen independence. In the present study, we generated tetracycline-inducible LNCaP-DDC prostate cancer stable cells to identify DDC downstream target genes by oligonucleotide microarray analysis.

Results: Comparison of induced DDC overexpressing cells versus non-induced control cell lines revealed a number of changes in the expression of androgen-regulated transcripts encoding proteins with a variety of molecular functions, including signal transduction, binding and catalytic activities. There were a total of 35 differentially expressed genes, 25 up-regulated and 10 down-regulated, in the DDC overexpressing cell line. In particular, we found a well-known androgen induced gene, TMEPAI, which wasup-regulated in DDC overexpressing cells, supporting its known co-activation function. In addition, DDC also further augmented the transcriptional repression function of AR for a subset of androgen-repressed genes. Changes in cellular gene transcription detected by microarray analysis were confirmed for selected genes by quantitative real-time RT-PCR.

Conclusion: Taken together, our results provide evidence for linking DDC action with AR signaling, which may be important for orchestrating molecular changes responsible for prostate cancer progression.

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Androgen-regulated and DDC-regulated genes. A) A Venn diagram analysis showing in yellow, the genes (130) with two fold induction in response to R1881 treatment in DDC overexpressing and control cells. The genes up- and down-regulated only in DDC overexpressing cells are represented in red (DDC; left) and the genes up- and down-regulated only in the control cells are represented in the green (controls; right). B) Reported here are 35 androgen-regulated genes differentially expressed at least 2-fold in DDC overexpressing cells (LNCaP-DDC) compared with the controls cells (LNCaP-CTRLs). The colors represent the ratio of gene expression levels in each cell line after R1881 treatment (red = hormone up-regulated and green = hormone down-regulated).
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Figure 4: Androgen-regulated and DDC-regulated genes. A) A Venn diagram analysis showing in yellow, the genes (130) with two fold induction in response to R1881 treatment in DDC overexpressing and control cells. The genes up- and down-regulated only in DDC overexpressing cells are represented in red (DDC; left) and the genes up- and down-regulated only in the control cells are represented in the green (controls; right). B) Reported here are 35 androgen-regulated genes differentially expressed at least 2-fold in DDC overexpressing cells (LNCaP-DDC) compared with the controls cells (LNCaP-CTRLs). The colors represent the ratio of gene expression levels in each cell line after R1881 treatment (red = hormone up-regulated and green = hormone down-regulated).

Mentions: Among the androgen-regulated genes we identified, using Venn diagram analysis, 130 genes that were androgen-regulated in LNCaP-DDC and LNCaP control cells (Figure 4A). The hormone induction response of these 130 genes was substantiated by the altered expression of the classically androgen-regulated genes, such as PSA, FKBP5, NKX3A, TMEPAI, KLK2, ODC1, and TMPRSS2 (data not shown). Comparison of LNCaP-DDC and LNCaP control cells revealed a number of changes in the expression profile of these androgen-regulated genes. Out of the 130 genes, 35 were differentially regulated as shown in Table 1. Of these, 25 genes were up-regulated at least two fold and 10 were down-regulated by at least two fold with DDC overexpression. In particular, among the set of 35 genes, we could identify four different responses to hormone treatment and DDC overexpression: i) 2 genes were hormone and DDC up-regulated ii) 4 genes were hormone and DDC down-regulated iii) 23 genes were hormone down-regulated in control cells and hormone up-regulated in DDC overexpressing cells iv) 6 genes were hormone up-regulated in control cells and hormone down-regulated in DDC overexpressing cells (Figure 4B).


Androgen-regulated genes differentially modulated by the androgen receptor coactivator L-dopa decarboxylase in human prostate cancer cells.

Margiotti K, Wafa LA, Cheng H, Novelli G, Nelson CC, Rennie PS - Mol. Cancer (2007)

Androgen-regulated and DDC-regulated genes. A) A Venn diagram analysis showing in yellow, the genes (130) with two fold induction in response to R1881 treatment in DDC overexpressing and control cells. The genes up- and down-regulated only in DDC overexpressing cells are represented in red (DDC; left) and the genes up- and down-regulated only in the control cells are represented in the green (controls; right). B) Reported here are 35 androgen-regulated genes differentially expressed at least 2-fold in DDC overexpressing cells (LNCaP-DDC) compared with the controls cells (LNCaP-CTRLs). The colors represent the ratio of gene expression levels in each cell line after R1881 treatment (red = hormone up-regulated and green = hormone down-regulated).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1904238&req=5

Figure 4: Androgen-regulated and DDC-regulated genes. A) A Venn diagram analysis showing in yellow, the genes (130) with two fold induction in response to R1881 treatment in DDC overexpressing and control cells. The genes up- and down-regulated only in DDC overexpressing cells are represented in red (DDC; left) and the genes up- and down-regulated only in the control cells are represented in the green (controls; right). B) Reported here are 35 androgen-regulated genes differentially expressed at least 2-fold in DDC overexpressing cells (LNCaP-DDC) compared with the controls cells (LNCaP-CTRLs). The colors represent the ratio of gene expression levels in each cell line after R1881 treatment (red = hormone up-regulated and green = hormone down-regulated).
Mentions: Among the androgen-regulated genes we identified, using Venn diagram analysis, 130 genes that were androgen-regulated in LNCaP-DDC and LNCaP control cells (Figure 4A). The hormone induction response of these 130 genes was substantiated by the altered expression of the classically androgen-regulated genes, such as PSA, FKBP5, NKX3A, TMEPAI, KLK2, ODC1, and TMPRSS2 (data not shown). Comparison of LNCaP-DDC and LNCaP control cells revealed a number of changes in the expression profile of these androgen-regulated genes. Out of the 130 genes, 35 were differentially regulated as shown in Table 1. Of these, 25 genes were up-regulated at least two fold and 10 were down-regulated by at least two fold with DDC overexpression. In particular, among the set of 35 genes, we could identify four different responses to hormone treatment and DDC overexpression: i) 2 genes were hormone and DDC up-regulated ii) 4 genes were hormone and DDC down-regulated iii) 23 genes were hormone down-regulated in control cells and hormone up-regulated in DDC overexpressing cells iv) 6 genes were hormone up-regulated in control cells and hormone down-regulated in DDC overexpressing cells (Figure 4B).

Bottom Line: There were a total of 35 differentially expressed genes, 25 up-regulated and 10 down-regulated, in the DDC overexpressing cell line.In particular, we found a well-known androgen induced gene, TMEPAI, which wasup-regulated in DDC overexpressing cells, supporting its known co-activation function.In addition, DDC also further augmented the transcriptional repression function of AR for a subset of androgen-repressed genes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. katia.margiotti@vch.ca

ABSTRACT

Background: The androgen receptor is a ligand-induced transcriptional factor, which plays an important role in normal development of the prostate as well as in the progression of prostate cancer to a hormone refractory state. We previously reported the identification of a novel AR coactivator protein, L-dopa decarboxylase (DDC), which can act at the cytoplasmic level to enhance AR activity. We have also shown that DDC is a neuroendocrine (NE) marker of prostate cancer and that its expression is increased after hormone-ablation therapy and progression to androgen independence. In the present study, we generated tetracycline-inducible LNCaP-DDC prostate cancer stable cells to identify DDC downstream target genes by oligonucleotide microarray analysis.

Results: Comparison of induced DDC overexpressing cells versus non-induced control cell lines revealed a number of changes in the expression of androgen-regulated transcripts encoding proteins with a variety of molecular functions, including signal transduction, binding and catalytic activities. There were a total of 35 differentially expressed genes, 25 up-regulated and 10 down-regulated, in the DDC overexpressing cell line. In particular, we found a well-known androgen induced gene, TMEPAI, which wasup-regulated in DDC overexpressing cells, supporting its known co-activation function. In addition, DDC also further augmented the transcriptional repression function of AR for a subset of androgen-repressed genes. Changes in cellular gene transcription detected by microarray analysis were confirmed for selected genes by quantitative real-time RT-PCR.

Conclusion: Taken together, our results provide evidence for linking DDC action with AR signaling, which may be important for orchestrating molecular changes responsible for prostate cancer progression.

Show MeSH
Related in: MedlinePlus