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

Keren Imberg-Kazdan, Susan Ha, Alex Greenfield, Christopher S. Poultney, Richard Bonneau, Susan K. Logan, Michael J. Garabedian

Research output: Contribution to journalArticle

Abstract

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 castrationresistant 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.

Original languageEnglish (US)
Pages (from-to)581-591
Number of pages11
JournalGenome Research
Volume23
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

Androgen Receptors
RNA Interference
Prostatic Neoplasms
Genome
Castration
Androgens
Mediator Complex
Gene Components
Protein Kinases
Genes
Drosophila
Phosphotransferases

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Imberg-Kazdan, K., Ha, S., Greenfield, A., Poultney, C. S., Bonneau, R., Logan, S. K., & Garabedian, M. J. (2013). A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells. Genome Research, 23(4), 581-591. https://doi.org/10.1101/gr.144774.112

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.

In: Genome Research, Vol. 23, No. 4, 04.2013, p. 581-591.

Research output: Contribution to journalArticle

Imberg-Kazdan, K, Ha, S, Greenfield, A, Poultney, CS, Bonneau, R, Logan, SK & Garabedian, MJ 2013, 'A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells', Genome Research, vol. 23, no. 4, pp. 581-591. https://doi.org/10.1101/gr.144774.112
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. In: Genome Research. 2013 ; Vol. 23, No. 4. pp. 581-591.
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