Identification of a RhoA- and SRF-Dependent Mechanism of Androgen Action that is Associated with Prostate Cancer Progression

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.