The Hippo Pathway in Prostate Cancer

Abstract

Despite recent efforts, prostate cancer (PCa) remains one of the most common cancers in men. Currently, there is no effective treatment for castration-resistant prostate cancer (CRPC). There is, therefore, an urgent need to identify new therapeutic targets. The Hippo pathway and its downstream effectors-the transcriptional co-activators, Yes-associated protein (YAP) and its paralog, transcriptional co-activator with PDZ-binding motif (TAZ)-are foremost regulators of stem cells and cancer biology. Defective Hippo pathway signaling and YAP/TAZ hyperactivation are common across various cancers. Here, we draw on insights learned from other types of cancers and review the latest advances linking the Hippo pathway and YAP/TAZ to PCa onset and progression. We examine the regulatory interaction between Hippo-YAP/TAZ and the androgen receptor (AR), as main regulators of PCa development, and how uncontrolled expression of YAP/TAZ drives castration resistance by inducing cellular stemness. Finally, we survey the potential therapeutic targeting of the Hippo pathway and YAP/TAZ to overcome PCa.

Keywords: YAP/TAZ; castration resistance; feedback loops; hippo pathway; prostate cancer; signal cross-talk.

Figure 1

Representation of different cell types in the prostate gland.

Figure 2

Schematic overview of YAP activity levels across different stages of prostate cancer (PCa). YAP regulates multiple stages of PCa [68,70,71].

Figure 3

Mechanisms of YAP regulation in early stages of prostate cancer. a. Heat shock protein 27 (Hsp27) induces MST1 ubiquitin-mediated degradation, which in turn causes LATS1 and MOB1 dephosphorylation and thereby inactivation, consequently inducing YAP nuclear translocation [88]. b. Two different mechanisms were proposed by which polarity protein (Par3) regulates YAP; (1) Par3 inhibits YAP activity through inducing the recruitment of Neurofibromatosis type 2 (NF2/Merlin) and LATS1 to the membrane. As a result, LATS1 is activated, which induces YAP phosphorylation and cytoplasmic retention [83]. (2) Par3 induces YAP activation through the dissociation of kidney- and brain-expressed protein (KIBRA) from its canonical complex (KIBRA/NF2/ FERM domain-containing protein 6 (FRDM6)) and drives the recruitment of KIBRA to the Par3/aPKC/KIBRA complex. Thus, the interaction between KIBRA and LATS1 is disrupted, which induces LATS1 dephosphorylation and thereby YAP activation [84]. c. E26 transformation-specific (ETS) transcription factors trigger YAP induction. (1) ETS-regulated gene (ERG) activation drives YAP activation in old aged mice. ERG induces YAP and TEAD4 promoter activity and thereby triggers YAP target gene expression [75]. (2) ETS translocation variant 1 (ETV1) drives YAP activation by recruiting lysine specific demethylase (JMJD2A) to the YAP promoter [77].

Figure 4

The Hippo pathway regulation of advanced prostate cancer. a. During androgen deprivation, Wingless (WNT) signaling drives the nuclear translocation of YAP and AR, resulting in YAP and AR target gene induction [143]. Additionally, YAP and AR colocalize in the nucleus and induce gene expression independently from WNT signaling or androgen availability [98]. b. α3β1 integrin stimulates the kinase activity of Arg/Abl, which phosphorylates 190RhoGAP, resulting in the inhibition of RhoA GTPases. Consequently, YAP/TAZ are phosphorylated via LATS1 activity and/or actin rearrangement and retained in the cytoplasm. α3β1 loss results in the disruption of this signaling cascade, inducing prostate cellular migration and metastasis [127]. c. PTEN and SMAD4 activity loss results in YAP hyperactivation. YAP signaling induces the recruitment of inflammatory cells [131]. d. LAST2 impedes AR receptor activity and restricts the binding of AR to the prostate-specific antigen (PSA) promoter [108]. e. EZH2 and c-MYC cooperate to induce methylation and silencing of MST1, which might induce AR activity [101]. g. ETV1/4/5 activate TAZ, triggering metastasis via the induction of SH3BP1 [141].

Figure 5

YAP/TAZ regulate prostate cancer stem cells (PCSCs). a. Inhibition of the stemness regulator cyclic GMP-specific phosphodiesterase type 5 (PDE5) by nitric oxide causes activation of cGMP-dependent protein G (PKG), which activates MST1/LATS1 and causes TAZ phosphorylation [154]. b. Stemness regulator microRNA (miR)-302–367 cluster induces LATS2 dephosphorylation which results in YAP nuclear translocation [153]. c. DNMT3a and EZH2 form a heterotrimeric complex with AR, which translocates to the YAP promoter inducing its silencing [155].