Abstract
Castration resistant prostate cancer (CRPC) is a stage of relapse that arises after various forms of androgen ablation therapy (ADT) and causes significant morbidity and mortality. However, the mechanism underlying progression to CRPC remains poorly understood. Here, we report that YAP1, which is negatively regulated by AR, influences prostate cancer (PCa) cell self-renewal and CRPC development. Specifically, we found that AR directly regulates the methylation of YAP1 gene promoter via the formation of a complex with Polycomb group protein EZH2 and DNMT3a. In normal conditions, AR recruits EZH2 and DNMT3a to YAP1 promoter, thereby promoting DNA methylation and the repression of YAP1 gene transcription. Following ADT treatment or when AR activity is antagonized by Bicalutamide or Enzalutamide, YAP1 gene expression is switched on. In turn, YAP1 promotes SOX2 and Nanog expression and the de-differentiation of PCa cells to stem/progenitor-like cells (PCSC), which potentially contribute to disease recurrence. Finally, the knock down of YAP1 expression or the inhibition of YAP1 function by Verteporfin in TRAMP prostate cancer mice significantly suppresses tumor recurrence following castration. In conclusion, our data reveals that AR suppresses YAP1 gene expression through a novel epigenetic mechanism, which is critical for PCa cells self-renewal and the development of CRPC.
Highlights
The development of lethal Castration resistant prostate cancer (CRPC) is driven by complex genetic and epigenetic mechanisms that remain poorly understood [1,2,3,4,5]
Our data reveals that AR suppresses YAP1 gene expression through a novel epigenetic mechanism, which is critical for prostate cancer (PCa) cells self-renewal and the development of CRPC
We examined the expression of bona fide stem cell markers, including Oct4, Nanog, Figure 3: The essential role of the AR–DNMT3a and EZH2 complex in the regulation of YAP1 expression. (A) Immunoprecipitation of AR in LNCaP cells followed by immunoblot analysis of EZH2, DNMT3a
Summary
The development of lethal CRPC is driven by complex genetic and epigenetic mechanisms that remain poorly understood [1,2,3,4,5]. We identified the involvement of YAP1, a key effector of the Hippo signaling pathway in the regulation of CRPC growth [6]. Nuclear YAP1 accumulates in CRPC and the inhibition of YAP1 function with Verteporfin www.impactjournals.com/oncotarget reduces the growth of androgen insensitive tumors in vivo [6]. In mouse models of PCa, YAP1 can regulate the recruitment of polymorphonuclear myeloid-derived suppressor cells, which promotes tumor growth [12]. Given these initial findings, it is clear that YAP1 mode of regulation and mechanism of action in urological malignancies merits additional studies
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