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

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.

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Cold Atmospheric Plasma Selectively Induces G0/G1 Cell Cycle Arrest and Apoptosis in AR-Independent Prostate Cancer Cells

10.21203/rs.3.rs-49986/v1 ◽

2020 ◽

Author(s):

Meng Ning ◽

Zhifa Zhang ◽

Lihui Yu ◽

Peiyu Han ◽

xiaofeng Dai

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Androgen Receptor ◽

Cancer Cells ◽

Atmospheric Plasma ◽

Prostate Cancer Cells ◽

Cold Atmospheric Plasma ◽

Prostate Cancers ◽

And Migration ◽

Physical Plasma

Abstract BackgroundAndrogen receptor-independent prostate cancers do not respond to androgen blockage therapies and suffer from high recurrence rate. We aim to contribute to the establishment of novel therapeutic approaches against such malignancies.Methods We examined whether and how cold atmospheric plasma delivers selectivity against AR-independent prostate cancers using human normal epithelial prostatic cells PNT1A and AR-negative DU145 prostate cancer cells.ResultsWe show that cold atmospheric plasma could selectively halt cell proliferation and migration in androgen receptor-independent cells as a result of induced cell apoptosis and G0/G1 stage cell cycle arrest, and such outcomes were achieved through modulations on the MAPK and NF-kB pathways in response to physical plasma induced intracellular redox level. ConclusionOur study reports cold atmospheric plasma induced reduction on the proliferation and migration of androgen receptor-independent prostate cancer cells that offers novel therapeutic insights on the treatment of such cancers, and provides the first evidence on physical plasma induced cell cycle G0/G1 stage arrest that warrants the exploration on the synergistic use of cold atmospheric plasma and drugs such as chemotherapies in eradicating such cancer cells.

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Transcriptional regulation of the TGF-β1 promoter by androgen receptor

Biochemical Journal ◽

10.1042/bj20080651 ◽

2008 ◽

Vol 416 (3) ◽

pp. 453-462 ◽

Cited By ~ 30

Author(s):

Wei Qi ◽

Shen Gao ◽

Zhengxin Wang

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Transforming Growth Factor ◽

Prostate Gland ◽

Transforming Growth Factor Β1 ◽

Prostate Cancer Cells ◽

Level Of Activity ◽

High Level ◽

Tgf Β1

TGF (transforming growth factor)-β1 is a multifunctional cytokine that influences homoeostatic processes of various tissues. TGF-β1 expression is inhibited by androgens in the prostate gland, whereas its expression is enhanced by androgens in highly metastatic prostate cancer cells. Here, we examined regulation of human TGF-β1 promoter activity by androgen in prostate cancer cells. The full-length (−3363 to +110) promoter showed a high level of activity in response to androgen in PC3mm2 cells expressing AR (androgen receptor). Further deletion analysis revealed three distal and three proximal AREs (androgen-response elements) in the promoter. Gel-shift and footprint assays show that these AREs physically interact with the DNA-binding domain of AR. Chromatin immunoprecipitation assays revealed the androgen-dependent recruitment of AR to the ARE-containing regions of the TGF-β1 gene. More importantly, a negative ARE was detected in the TGF-β1 promoter. Both positive and negative AREs are functional in the androgen-regulated transcription of the TGF-β1 promoter. These findings imply that androgen signalling may positively or negatively regulate TGF-β1 expression in response to various signals or under different environmental conditions.

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Geldanamycin downregulates androgen receptor-mediated transcriptional activation in human prostate cancer cells by inhibiting AR nuclear translocation

Journal of the American College of Surgeons ◽

10.1016/s1072-7515(00)00667-0 ◽

2000 ◽

Vol 191 (4) ◽

pp. S93-S94

Author(s):

Yaxin Zheng ◽

Jerome P Richie ◽

Michael L Lu

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Transcriptional Activation ◽

Nuclear Translocation ◽

Human Prostate ◽

Human Prostate Cancer ◽

Prostate Cancer Cells

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

Journal of Molecular Endocrinology ◽

10.1677/jme-07-0158 ◽

2008 ◽

Vol 41 (1) ◽

pp. 13-23 ◽

Cited By ~ 8

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.

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