YAP1 regulates prostate cancer stem cell-like characteristics to promote castration resistant growth
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YAP1 regulates prostate cancer stem cell-like characteristics to promote castration resistant growth. / Jiang, Ning; Ke, Binghu; Hjort-Jensen, Kim; Iglesias-Gato, Diego; Wang, Zhun; Chang, Pengcheng; Zhao, Yang; Niu, Xiaodan; Wu, Tao; Peng, Bo; Jiang, Mingdong; Li, Xiaoshi; Shang, Zhiqun; Wang, Qiang; Chang, Chawnshang; Flores-Morales, Amilcar; Niu, Yuanjie.
I: OncoTarget, Bind 8, Nr. 70, 2017, s. 115054-115067.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
VL - 8
SP - 115054
EP - 115067
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 70
ER -
ID: 188230457