Abstract
The transcriptional co-activator Yes-associated protein 1 (YAP1), a key nuclear effector of the Hippo pathway, is a potent oncogene, and yet, the interaction between YAP1 and androgen receptor (AR) remains unexplored. Here we identify YAP1 as a physiological binding partner and positive regulator of AR in prostate cancer. YAP1 and AR co-localize and interact with each other predominantly within cell nuclei by an androgen-dependent mechanism in a hormone naive and an androgen-independent mechanism in castration-resistant prostate cancer cells. The growth suppressor MST1 kinase modulates androgen-dependent and -independent nuclear YAP1-AR interactions through directly regulating YAP1 nuclear accumulation. Disruption of YAP1 signalling by genetic (RNAi) and pharmacological (Verteporfin) approaches suppresses AR-dependent gene expression and prostate cancer cell growth. These findings indicate that the YAP1-AR axis may have a critical role in prostate cancer progression and serves as a viable drug target.
Highlights
The transcriptional co-activator Yes-associated protein 1 (YAP1), a key nuclear effector of the Hippo pathway, is a potent oncogene, and yet, the interaction between YAP1 and androgen receptor (AR) remains unexplored
We assessed the expression of YAP1 protein in the histologic sections of normal prostate (NP) and Prostate cancer (PC) tissues by immunohistochemistry (IHC)
In the current study, we have demonstrated that a nuclear interaction between YAP1 and AR that is regulated by MST1 signalling, possibly via a LATS1/2 bypass mechanism, may play a prominent role in the emergence of advanced PC
Summary
The transcriptional co-activator Yes-associated protein 1 (YAP1), a key nuclear effector of the Hippo pathway, is a potent oncogene, and yet, the interaction between YAP1 and androgen receptor (AR) remains unexplored. Disruption of YAP1 signalling by genetic (RNAi) and pharmacological (Verteporfin) approaches suppresses AR-dependent gene expression and prostate cancer cell growth. These findings indicate that the YAP1–AR axis may have a critical role in prostate cancer progression and serves as a viable drug target. AR gene amplification[4], and mutations[5] that increase or decrease sensitivity and/or specificity to its ligands[6], oncogenic growth factor signalling[7], and altered AR co-regulators[8] have been shown to cause an aberrant AR activation, even in the presence of very little androgens in circulation[9,10]. We show that MST1 is a key negative regulator of YAP1–AR interactions, which may play crucial role in AR-dependent gene expression and PC cell growth in vitro and in vivo. Our study identifies new functions of the YAP1 interaction with AR
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