Oncotarget

Research Papers:

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

Ning Jiang, Binghu Ke, Kim Hjort-Jensen, Diego Iglesias-Gato, Zhun Wang, Pengcheng Chang, Yang Zhao, Xiaodan Niu, Tao Wu, Bo Peng, Mingdong Jiang, Xiaoshi Li, Zhiqun Shang, Qiang Wang, Chawnshang Chang, Amilcar Flores-Morales and Yuanjie Niu _

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Oncotarget. 2017; 8:115054-115067. https://doi.org/10.18632/oncotarget.23014

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Abstract

Ning Jiang1, Binghu Ke1, Kim Hjort-Jensen2,3, Diego Iglesias-Gato2,3, Zhun Wang1, Pengcheng Chang1, Yang Zhao1, Xiaodan Niu4, Tao Wu1, Bo Peng1, Mingdong Jiang1, Xiaoshi Li1, Zhiqun Shang1, Qiang Wang1, Chawnshang Chang5, Amilcar Flores-Morales2,3 and Yuanjie Niu1

1Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China

2Department of Drug Design and Pharmacology, Københavns Universitet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

3Danish Cancer Society, Copenhagen, Denmark

4University of Minnesota, Minneapolis, MN, USA

5University of Rochester, Rochester, NY, USA

Correspondence to:

Yuanjie Niu, email: niuyuanjie9317@126.com

Amilcar Flores-Morales, email: Amilcar.Flores@cpr.ku.dk

Keywords: prostate cancer; YAP1; androgen receptor; DNA methylation; castration resistant prostate cancer

Received: September 11, 2017     Accepted: October 29, 2017     Published: December 07, 2017

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.


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