YAP1 regulates prostate cancer stem cell-like characteristics to promote castration resistant growth
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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
Yuanjie Niu, email: [email protected]
Amilcar Flores-Morales, email: [email protected]
Keywords: prostate cancer; YAP1; androgen receptor; DNA methylation; castration resistant prostate cancer
Received: September 11, 2017 Accepted: October 29, 2017 Published: December 07, 2017
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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