YAP1 regulates prostate cancer stem cell-like characteristics to promote castration resistant growth

TY - JOUR

T1 - YAP1 regulates prostate cancer stem cell-like characteristics to promote castration resistant growth

AU - Jiang, Ning

AU - Ke, Binghu

AU - Hjort-Jensen, Kim

AU - Iglesias-Gato, Diego

AU - Wang, Zhun

AU - Chang, Pengcheng

AU - Zhao, Yang

AU - Niu, Xiaodan

AU - Wu, Tao

AU - Peng, Bo

AU - Jiang, Mingdong

AU - Li, Xiaoshi

AU - Shang, Zhiqun

AU - Wang, Qiang

AU - Chang, Chawnshang

AU - Flores-Morales, Amilcar

AU - Niu, Yuanjie

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Androgen receptor

KW - Castration resistant prostate cancer

KW - DNA methylation

KW - Prostate cancer

KW - YAP1

U2 - 10.18632/oncotarget.23014

DO - 10.18632/oncotarget.23014

M3 - Journal article

C2 - 29383141

AN - SCOPUS:85039742594

SN - 1949-2553

VL - 8

SP - 115054

EP - 115067

JO - Oncotarget

JF - Oncotarget

IS - 70

ER -