Androgen receptor splice variants activate androgen receptor target genes and support aberrant prostate cancer cell growth independent of canonical androgen receptor nuclear localization signal

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Journal of Biological Chemistry (Impact Factor: 4.6). 04/2012; 287(23):19736-49. DOI: 10.1074/jbc.M112.352930
Source: PubMed

ABSTRACT Synthesis of truncated androgen receptor (AR) splice variants has emerged as an important mechanism of prostate cancer (PCa) resistance to AR-targeted therapy and progression to a lethal castration-resistant phenotype. However, the precise role of these factors at this stage of the disease is not clear due to loss of multiple COOH-terminal AR protein domains, including the canonical nuclear localization signal (NLS) in the AR hinge region. Despite loss of this NLS, we show that diverse truncated AR variant species have a basal level of nuclear localization sufficient for ligand-independent transcriptional activity. Whereas full-length AR requires Hsp90 and importin-β for active nuclear translocation, basal nuclear localization of truncated AR variants is independent of these classical signals. For a subset of truncated AR variants, this basal level of nuclear import can be augmented by unique COOH-terminal sequences that reconstitute classical AR NLS activity. However, this property is separable from ligand-independent transcriptional activity. Therefore, the AR splice variant core consisting of the AR NH(2)-terminal domain and DNA binding domain is sufficient for nuclear localization and androgen-independent transcriptional activation of endogenous AR target genes. Indeed, we show that truncated AR variants with nuclear as well as nuclear/cytoplasmic localization patterns can drive androgen-independent growth of PCa cells. Together, our data demonstrate that diverse truncated AR species with varying efficiencies of nuclear localization can contribute to castration-resistant PCa pathology by driving persistent ligand-independent AR transcriptional activity.

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    • "Moreover, it was recently shown that truncated forms of AR with intact NH 2 -terminal and DNA binding domains are constitutively active and able to maintain androgen-independent transcriptional activation of endogenous AR target genes, thus supporting androgen-independent growth of PCa cells (Chan et al., 2012). The expression of these forms is associated with a poor prognosis and they have been recognized Fig. 2 "
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    • "The biological and clinical significance of differential expression of isoform variants is illustrated, for example, by the bcl-2 apoptotic gene family member bcl-x [3], for which the short (xS) and long (xL) variants are pro-and antiapoptotic, respectively. In prostate cancer, one of the most clinically relevant examples of differential expression of isoform variants has only recently been characterized for the androgen receptor (AR) [4] [5] [6]. While expression of the main isoform variant of AR is tightly coupled to sensitivity to antiandrogen therapy (AAT), the truncated v567 variant functions as a constitutively active, ligandindependent transcription factor that can support androgenindependent growth and progression of castrate-resistant metastatic prostate cancer. "
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