Role of androgen receptor co-repressor SLIRP in cell cycle regulation Public Deposited

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  • March 20, 2019
  • De Silva, Dinuka
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
  • Androgen receptor (AR) reactivation is a hallmark of castration resistant prostate cancer (CRPC). One mechanism is tyrosine kinase Ack1 mediated activation phosphorylation of Tyr-267 and Tyr-363 residues on AR. Investigation into Ack1 regulation of AR identified SLIRP as a potential AR interacting protein. SLIRP acts as a co-repressor of steroid receptor signaling. We show that SLIRP interacted with AR in the absence of Ack1 activation, repressing AR signaling. In the presence of either androgen or Ack1 kinase activation, SLIRP dissociated from the complex and AR signaling was activated. SLIRP dissociation from AR was dependent on the kinase activity of Ack1 but not the known Ack1 phosphorylation sites of Tyr-267 and Tyr-363 of AR. Furthermore, SLIRP-AR binding was dependent on RNA co-regulator SRA in AR signaling as knockdown of SRA resulted in reduced SLIRP co-immunoprecipitation with AR. Microarray and RNA-seq gene expression profiling of LNCaP cells with SLIRP knockdown generated a large gene list. One major affected pathway was the cell cycle pathway. LNCaP and LAPC4 cells treated with SLIRP siRNA demonstrated increased phosphorylation of Rb protein, enhanced cell proliferation, and increases in CDK1 and CDK6, cyclins E1, A2, and E2F1 and E2F2 mRNA levels. In addition, cell cycle analysis demonstrated an increased number of cells in S-phase with SLIRP knockdown, compared to control. Investigation of other known AR co-repressors, NCoR1 and SMRT, did not demonstrate a similar role in cell cycle. However, knockdown of co-repressor SHARP showed an effect on cell cycle by increased phospho-Rb protein and S-phase entry, but to a lesser extent than SLIRP. AR negative PC3 and DU145 cells did not recapitulate the results in LNCaP cells, suggesting AR dependence in the role of SLIRP in cell cycle. In conclusion, we define a novel mechanism in which AR activity is regulated by SLIRP binding that is disrupted by Ack1 kinase or androgen. Ack1 gene amplification or AR mutations seen in CRPC may confer sensitivity of AR to low levels of androgens. Hence, our data suggests that disruption of SLIRP repression of AR-dependent transcription may be a potential mechanism of inappropriate restoration of AR signaling in CRPC.
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  • In Copyright
  • Whang, Young E.
  • Doctor of Philosophy
Graduation year
  • 2014

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