Title:Identification of a RhoA- and SRF-Dependent Mechanism of Androgen Action that is Associated with Prostate Cancer Progression
Volume: 14
Issue: 4
Author(s): Hannelore V. Heemers
Affiliation:
Keywords:
Androgen deprivation therapy, hormones, prostate cancer, treatment
Abstract: Androgen receptor (AR) action is critical for prostate cancer (CaP) progression, but is not inhibited fully by
available androgen deprivation therapy (ADT). One of the limitations to current ADT is that it targets all androgen action
in CaP, and other, cells irrespective of clinical relevance. The resulting off-target effects are responsible for ADTassociated
side effects that affect negatively a patient’s quality of life. Isolation of the AR-dependent events that drive CaP
progression may lead to novel forms of ADT that are at least as effective but more selective. Here, an approach is described
that starts from insights in the basic mechanism(s) by which AR regulates target gene expression to identify novel
drugable targets downstream of AR. Exploration of the molecular events that underlie androgen regulation of the ARassociated
coregulator FHL2 led to the isolation of a novel indirect mechanism of androgen action that is mediated by the
secondary transcription factor Serum Response Factor (SRF). Using a combination of oligoarray and in silico analyses, an
SRF-dependent fraction of AR action was identified that is enriched in CaP tissues, is able to discriminate between benign
and malignant prostate, and correlates with aggressive disease and biochemical failure. The RhoA signaling axis, a wellknown
upstream stimulator of SRF action that harbors drugable targets, conveyed androgen-responsiveness to SRF, and
was activated in CaP where it correlates with increased CaP aggressiveness and poor outcome after surgery.
