Abstract
Aberrant activation of the androgen receptor (AR) may play a critical role in castration resistant prostate cancer. After ligand binding, AR is recruited to the androgen responsive element (ARE) sequences on the DNA where AR interaction with coactivators and corepressors modulates transcription. We demonstrated that phosphorylation of AR at Tyr-267 by Ack1/TNK2 tyrosine kinase results in nuclear translocation, DNA binding, and androgen-dependent gene transcription in a low androgen environment. In order to dissect downstream mechanisms, we searched for proteins whose interaction with AR was regulated by Ack1. SLIRP (SRA stem-loop interacting RNA binding protein) was identified as a candidate protein. Interaction between AR and SLIRP was disrupted by Ack1 kinase activity as well as androgen or heregulin treatment. The noncoding RNA, SRA, was required for AR-SLIRP interaction. SLIRP was bound to ARE’s of AR target genes in the absence of androgen. Treatment with androgen or heregulin led to dissociation of SLIRP from the ARE. Whole transcriptome analysis of SLIRP knockdown in androgen responsive LNCaP cells showed that SLIRP affects a significant subset of androgen-regulated genes. Our data suggest that Ack1 kinase and androgen regulate interaction between AR and SLIRP and that SLIRP functions as a coregulator of AR with properties of a corepressor in a context-dependent manner.
Highlights
Aberrant activation of the androgen receptor (AR) may play a critical role in castration resistant prostate cancer
We have demonstrated that phosphorylation of AR at Tyr-267 by Ack[1] (TNK2) nonreceptor tyrosine kinase results in nuclear translocation, DNA binding, and transactivation of target genes in the low androgen environment[9,10]
In an attempt to identify AR interacting proteins regulated by Ack[1] kinase, we employed the differential in-gel electrophoresis (DIGE) approach to compare proteins co-immunoprecipitating with AR in 293 T cells transfected to express AR only versus AR and constitutively active Ack[1] (Supplementary Fig. S1)
Summary
Aberrant activation of the androgen receptor (AR) may play a critical role in castration resistant prostate cancer. The AR protein is a steroid receptor composed of three major domains, the N-terminal transactivation domain, the DNA-binding domain, and the C-terminal ligand binding domain[4] Binding of ligands such as dihydrotestosterone (DHT) to AR causes nuclear translocation and binding to the androgen responsive elements (ARE) of the target genes and assembly of the active transcription complex that contains general transcription factors and AR coregulators[5]. These coactivators and corepressors modulate AR-induced gene expression in prostate cancer cells and may play a role in development and progression of prostate cancer. We show that SLIRP associating with AR is influenced by Ack[1] kinase and androgen, which eject it from the AR complex, modulating AR signaling
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