Negative Regulation of the Androgen Receptor Gene Through a Primate-Specific Androgen Response Element Present in the 5′ UTR

Hay, Colin W.; Watt, Kate; Hunter, Irene; Lavery, Derek N.; MacKenzie, Alasdair; McEwan, Iain J.

doi:10.1007/s12672-014-0185-y

Cited by 16 publications

(24 citation statements)

References 60 publications

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“…LNCaP cells were treated with DMSO or 50 nM mithramycin A (Sigma) for 24 hours. Extraction of RNA and RT-PCR for AR and GAPDH mRNA were carried out as described previously [ 34 ].…”

Section: Methodsmentioning

confidence: 99%

“…Mutations of potential regulatory elements were introduced into plasmid phAR1.6Luc, in which luciferase expression is driven by 1.6 kbp of the promoter and 5’UTR of the human androgen receptor gene (between -741 and +842 bp) [ 34 ], using two methodologies. Base substitutions were created using the QuikChange II Mutagenesis kit (Agilent Technologies) using the oligonucleotides listed in Table A in S1 File , along with their reverse complements.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, Sp1 can form multimers and multiple stacked tetramers providing numerous docking sites for a variety of other proteins to regulate transcription both directly and through histone acetylation and chromatin remodelling (reviewed in [ 32 ]). In addition to the upregulatory GC boxes, the 5’UTR region encodes several inhibitory regulatory elements including a composite NF-κB, B-myb binding site [ 33 ], an negative ARE [ 34 ] and an Androgen Receptor Suppressor (ARS) [ 35 ] that binds pur-α and hnRNP-K on opposite strands of the DNA [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

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An Sp1 Modulated Regulatory Region Unique to Higher Primates Regulates Human Androgen Receptor Promoter Activity in Prostate Cancer Cells

et al. 2015

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Androgen receptor (AR) mediated signalling is necessary for normal development of the prostate gland and also drives prostate cancer (PCa) cell growth and survival, with many studies showing a correlation between increased receptor levels and therapy resistance with progression to fatal castrate recurrent PCa (CRPC). Although it has been held for some time that the transcription factor Sp1 is the main stimulator of AR gene transcription, comprehensive knowledge of the regulation of the AR gene remains incomplete. Here we describe and characterise in detail two novel active regulatory elements in the 5’UTR of the human AR gene. Both of these elements contain overlapping binding sites for the positive transcription factor Sp1 and the repressor protein pur-α. Aberrant cell signalling is characteristic of PCa and the transcriptional activity of the AR promoter in PCa cells is dependent upon the relative amounts of the two transcription factors. Together with our corroboration of the dominant role of Sp1, the findings support the rationale of targeting this transcription factor to inhibit tumour progression. This should be of particular therapeutic relevance in CRPC where the levels of the repressor pur-α are reduced.

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“…LNCaP cells were treated with DMSO or 50 nM mithramycin A (Sigma) for 24 hours. Extraction of RNA and RT-PCR for AR and GAPDH mRNA were carried out as described previously [ 34 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An Sp1 Modulated Regulatory Region Unique to Higher Primates Regulates Human Androgen Receptor Promoter Activity in Prostate Cancer Cells

et al. 2015

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“…Indirect upregulation through increased Zeb1 expression. (Cai et al 2011,Hay et al 2014,Dai and Burnstein 1996,Grad et al 1999 …”

mentioning

confidence: 99%

Tissue control of androgen action: The ups and downs of androgen receptor expression

Hunter

Hay

Esswein

et al. 2018

Molecular and Cellular Endocrinology

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Please cite this article as: Hunter, I., Hay, C.W., Esswein, B., Watt, K., McEwan, I.J., Tissue control of androgen action: The ups and downs of androgen receptor expression, Molecular and Cellular Endocrinology (2017), doi: 10.1016/j.mce.2017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…In agreement with our cell line data, castration significantly reduced Tmprss2 expression in the mouse lung ( Figure 5B). In the same mice, castration was also associated with an increase in Ar expression (P<0.01), expected as Ar gene transcription is downregulated in response to androgen [56].…”

Section: Tmprss2 Expression Is Reduced By Enzalutamide In Mouse Lungmentioning

confidence: 73%

TMPRSS2, required for SARS-CoV-2 entry, is downregulated in lung cells by enzalutamide, a prostate cancer therapeutic

Leach¹,

Isac²,

Bevan³

et al. 2020

Preprint

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The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, attacks various organs but most destructively the lung. It has been shown that SARS-CoV-2 entry into lung cells requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; activation of the androgen receptor increases TMPRSS2 levels in various tissues, most notably the prostate. We show here that treatment with the antiandrogen enzalutamide – a well-tolerated drug widely used in advanced prostate cancer – reduces TMPRSS2 levels in human lung cells. Further, enzalutamide treatment of mice dramatically decreased Tmprss2 levels in the lung. In support of this new experimental data, analysis of existing datasets shows striking co- expression of AR and TMPRSS2, including in specific lung cell types that are targeted by SARS- CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

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Negative Regulation of the Androgen Receptor Gene Through a Primate-Specific Androgen Response Element Present in the 5′ UTR

Cited by 16 publications

References 60 publications

An Sp1 Modulated Regulatory Region Unique to Higher Primates Regulates Human Androgen Receptor Promoter Activity in Prostate Cancer Cells

An Sp1 Modulated Regulatory Region Unique to Higher Primates Regulates Human Androgen Receptor Promoter Activity in Prostate Cancer Cells

Tissue control of androgen action: The ups and downs of androgen receptor expression

TMPRSS2, required for SARS-CoV-2 entry, is downregulated in lung cells by enzalutamide, a prostate cancer therapeutic

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