The
androgen receptor (AR) requires coregulators for its optimal function. However, whether AR coregulators further need interacting
protein(s) for their proper function remains unclear. Here we describe
transgelin as the first ARA54-associated negative modulator for AR.
Transgelin suppressed ARA54-enhanced AR function in ARA54-positive, but not in ARA54-negative, cells.
Transgelin suppressed AR transactivation via interruption of ARA54 homodimerization and AR-ARA54 heterodimerization, resulting in the cytoplasmic retention of AR and ARA54. Stable transfection of
transgelin in LNCaP cells suppressed AR-mediated cell growth and
prostate-specific antigen expression, whereas this suppressive effect was abolished by the addition of ARA54-small interfering
RNA. Results from tissue surveys showing decreased expression of
transgelin in
prostate cancer specimens further strengthened the suppressor role of
transgelin. Our findings reveal the novel mechanisms of how
transgelin functions as a suppressor to inhibit
prostate cancer cell growth. They also demonstrate that AR coregulators, like ARA54, might have dual in vivo roles functioning as both a direct coactivator and as an indirect mediator in AR function. The finding that a
protein can modulate AR function without direct interaction with AR might provide a new therapeutic approach, with fewer side effects, to battle
prostate cancer by targeting AR indirectly.