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A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells

The androgen receptor (AR) is a mediator of both androgen-dependent and castration-resistant prostate cancers. Identification of cellular factors affecting AR transcriptional activity could in principle yield new targets that reduce AR activity and combat prostate cancer, yet a comprehensive analysi...

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Autores principales: Imberg-Kazdan, Keren, Ha, Susan, Greenfield, Alex, Poultney, Christopher S., Bonneau, Richard, Logan, Susan K., Garabedian, Michael J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613576/
https://www.ncbi.nlm.nih.gov/pubmed/23403032
http://dx.doi.org/10.1101/gr.144774.112
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author Imberg-Kazdan, Keren
Ha, Susan
Greenfield, Alex
Poultney, Christopher S.
Bonneau, Richard
Logan, Susan K.
Garabedian, Michael J.
author_facet Imberg-Kazdan, Keren
Ha, Susan
Greenfield, Alex
Poultney, Christopher S.
Bonneau, Richard
Logan, Susan K.
Garabedian, Michael J.
author_sort Imberg-Kazdan, Keren
collection PubMed
description The androgen receptor (AR) is a mediator of both androgen-dependent and castration-resistant prostate cancers. Identification of cellular factors affecting AR transcriptional activity could in principle yield new targets that reduce AR activity and combat prostate cancer, yet a comprehensive analysis of the genes required for AR-dependent transcriptional activity has not been determined. Using an unbiased genetic approach that takes advantage of the evolutionary conservation of AR signaling, we have conducted a genome-wide RNAi screen in Drosophila cells for genes required for AR transcriptional activity and applied the results to human prostate cancer cells. We identified 45 AR-regulators, which include known pathway components and genes with functions not previously linked to AR regulation, such as HIPK2 (a protein kinase) and MED19 (a subunit of the Mediator complex). Depletion of HIPK2 and MED19 in human prostate cancer cells decreased AR target gene expression and, importantly, reduced the proliferation of androgen-dependent and castration-resistant prostate cancer cells. We also systematically analyzed additional Mediator subunits and uncovered a small subset of Mediator subunits that interpret AR signaling and affect AR-dependent transcription and prostate cancer cell proliferation. Importantly, targeting of HIPK2 by an FDA-approved kinase inhibitor phenocopied the effect of depletion by RNAi and reduced the growth of AR-positive, but not AR-negative, treatment-resistant prostate cancer cells. Thus, our screen has yielded new AR regulators including drugable targets that reduce the proliferation of castration-resistant prostate cancer cells.
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spelling pubmed-36135762013-10-01 A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells Imberg-Kazdan, Keren Ha, Susan Greenfield, Alex Poultney, Christopher S. Bonneau, Richard Logan, Susan K. Garabedian, Michael J. Genome Res Research The androgen receptor (AR) is a mediator of both androgen-dependent and castration-resistant prostate cancers. Identification of cellular factors affecting AR transcriptional activity could in principle yield new targets that reduce AR activity and combat prostate cancer, yet a comprehensive analysis of the genes required for AR-dependent transcriptional activity has not been determined. Using an unbiased genetic approach that takes advantage of the evolutionary conservation of AR signaling, we have conducted a genome-wide RNAi screen in Drosophila cells for genes required for AR transcriptional activity and applied the results to human prostate cancer cells. We identified 45 AR-regulators, which include known pathway components and genes with functions not previously linked to AR regulation, such as HIPK2 (a protein kinase) and MED19 (a subunit of the Mediator complex). Depletion of HIPK2 and MED19 in human prostate cancer cells decreased AR target gene expression and, importantly, reduced the proliferation of androgen-dependent and castration-resistant prostate cancer cells. We also systematically analyzed additional Mediator subunits and uncovered a small subset of Mediator subunits that interpret AR signaling and affect AR-dependent transcription and prostate cancer cell proliferation. Importantly, targeting of HIPK2 by an FDA-approved kinase inhibitor phenocopied the effect of depletion by RNAi and reduced the growth of AR-positive, but not AR-negative, treatment-resistant prostate cancer cells. Thus, our screen has yielded new AR regulators including drugable targets that reduce the proliferation of castration-resistant prostate cancer cells. Cold Spring Harbor Laboratory Press 2013-04 /pmc/articles/PMC3613576/ /pubmed/23403032 http://dx.doi.org/10.1101/gr.144774.112 Text en © 2013, Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/3.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.
spellingShingle Research
Imberg-Kazdan, Keren
Ha, Susan
Greenfield, Alex
Poultney, Christopher S.
Bonneau, Richard
Logan, Susan K.
Garabedian, Michael J.
A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells
title A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells
title_full A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells
title_fullStr A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells
title_full_unstemmed A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells
title_short A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells
title_sort genome-wide rna interference screen identifies new regulators of androgen receptor function in prostate cancer cells
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613576/
https://www.ncbi.nlm.nih.gov/pubmed/23403032
http://dx.doi.org/10.1101/gr.144774.112
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