scholarly journals TGFβ-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1

Cell Cycle ◽  
2014 ◽  
Vol 13 (15) ◽  
pp. 2400-2414 ◽  
Author(s):  
Noopur Thakur ◽  
Shyam Kumar Gudey ◽  
Anders Marcusson ◽  
Jing Yi Fu ◽  
Anders Bergh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Transcriptional Activation ◽  
Prostate Cancer Cells

Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 in prostate cancer cells

2010 ◽  
Vol 433 (1) ◽  
pp. 225-233 ◽  
Author(s):  
Jong-Seok Moon ◽  
Won-Ji Jin ◽  
Jin-Hye Kwak ◽  
Hyo-Jeong Kim ◽  
Mi-Jin Yun ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Transcriptional Activation ◽  
De Novo ◽  
Lipid Synthesis ◽  
Signalling Pathway ◽  
De Novo Lipogenesis ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
Hexokinase 2

Up-regulation of lipogenesis by androgen is one of the most characteristic metabolic features of LNCaP prostate cancer cells. The present study revealed that androgen increases glucose utilization for de novo lipogenesis in LNCaP cells through the activation of HK2 (hexokinase 2) and activation of the cardiac isoform of PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase). Activation of PKA (cAMP-dependent protein kinase) by androgen increased phosphorylation of CREB [CRE (cAMP-response element)-binding protein], which in turn bound to CRE on the promoter of the HK2 gene resulting in transcriptional activation of the HK2 gene. Up-regulation of PFKFB2 expression was mediated by the direct binding of ligand-activated androgen receptor to the PFKFB2 promoter. The activated PI3K (phosphoinositide 3-kinase)/Akt signalling pathway in LNCaP cells contributes to the phosphorylation of PFKFB2 at Ser466 and Ser483, resulting in the constitutive activation of PFK-2 (6-phosphofructo-2-kinase) activity. Glucose uptake and lipogenesis were severely blocked by knocking-down of PFKFB2 using siRNA (small interfering RNA) or by inhibition of PFK-2 activity with LY294002 treatment. Taken together, our results suggest that the induction of de novo lipid synthesis by androgen requires the transcriptional up-regulation of HK2 and PFKFB2, and phosphorylation of PFKFB2 generated by the PI3K/Akt signalling pathway to supply the source for lipogenesis from glucose in prostate cancer cells.

scholarly journals Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells

2008 ◽  
Vol 41 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Chen-Lin Hsieh ◽  
Changmeng Cai ◽  
Ahmed Giwa ◽  
Aaronica Bivins ◽  
Shao-Yong Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Transcriptional Activation ◽  
Soluble Guanylyl Cyclase ◽  
Growth Conditions ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
Transcriptional Activation Domain ◽  
Androgen Independent

Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-α1 (sGCα1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCα1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNAI-dependent inhibition of sGCα1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCα1 in the androgen-independent growth of these cells.

scholarly journals Activation of the Androgen Receptor gene by BORIS/CTCFL in prostate cancer cells

2017 ◽  
Author(s):  
Yukti Hari-Gupta ◽  
Georgia-Xanthi Kita ◽  
Dawn Farrar ◽  
Elena Klenova
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Transcriptional Activation ◽  
Critical Role ◽  
Prostate Gland ◽  
Biologically Active ◽  
Ctcf Binding ◽  
Prostate Cancer Cells ◽  
Prostate Cancers

AbstractBORIS/CTCFL, a paralogue of the chromatin architectural protein CTCF, is a member of the cancer-testis antigen family, normally present in the testes. BORIS is expressed in various tumours, including prostate cancers, however the function of BORIS in cancer cells is not well defined. The androgen receptor (AR) plays a critical role in the normal development of a human prostate gland and pathogenesis of prostate cancer. In our previous study we described a positive correlation between elevated levels of BORIS and AR in prostate cancers, and activation of the AR gene by BORIS in prostate cancer cells. Elucidation of the mechanisms involved in the modulation of AR activity is important to understand prostate tumourigenesis and investigation of transcriptional regulation of the AR gene by BORIS may provide new insights into this issue. Here we report the ability of BORIS to not only positively regulate AR in androgen-dependent prostate cancer (ADPC) cells, but re-activate epigenetically silenced AR in androgen-independent prostate cancer (AIPC) cells leading to the production of biologically active AR protein. CTCF, on the other hand, had repressive effects on the AR. In both, ADPC and AIPC cells, introduction of ectopic BORIS was associated with the reduction in the AR promoter methylation, increase in active and decrease in repressive chromatin marks, and decrease in CTCF occupancies at the two main upstream BORIS/CTCF binding sites. We propose a model of epigenetic regulation of AR by BORIS in prostate cells whereby BORIS remodels the chromatin at the AR promoter leading to transcriptional activation.

scholarly journals Long Terminal Repeats Act as Androgen-Responsive Enhancers for the PSA-Kallikrein Locus

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3199-3210 ◽  
Author(s):  
Mitchell G. Lawrence ◽  
Carson R. Stephens ◽  
Eleanor F. Need ◽  
John Lai ◽  
Grant Buchanan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Specific Antigen ◽  
Endogenous Retrovirus ◽  
Repetitive Elements ◽  
Prostate Cancer Cells ◽  
Distal Enhancer ◽  
Detailed Understanding

The androgen receptor (AR) signaling pathway is a common therapeutic target for prostate cancer, because it is critical for the survival of both hormone-responsive and castrate-resistant tumor cells. Most of the detailed understanding that we have of AR transcriptional activation has been gained by studying classical target genes. For more than two decades, Kallikrein 3 (KLK3) (prostate-specific antigen) has been used as a prototypical AR target gene, because it is highly androgen responsive in prostate cancer cells. Three regions upstream of the KLK3 gene, including the distal enhancer, are known to contain consensus androgen-responsive elements required for AR-mediated transcriptional activation. Here, we show that KLK3 is one of a specific cluster of androgen-regulated genes at the centromeric end of the kallikrein locus with enhancers that evolved from the long terminal repeat (LTR) (LTR40a) of an endogenous retrovirus. Ligand-dependent recruitment of the AR to individual LTR-derived enhancers results in concurrent up-regulation of endogenous KLK2, KLK3, and KLKP1 expression in LNCaP prostate cancer cells. At the molecular level, a kallikrein-specific duplication within the LTR is required for maximal androgen responsiveness. Therefore, KLK3 represents a subset of target genes regulated by repetitive elements but is not typical of the whole spectrum of androgen-responsive transcripts. These data provide a novel and more detailed understanding of AR transcriptional activation and emphasize the importance of repetitive elements as functional regulatory units.

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