Researchers in Section of Pharmacotherapy – University of Copenhagen

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

Research output: Contribution to journalJournal articleResearchpeer-review

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, Yuanjie Niu

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.

Original languageEnglish
Issue number70
Pages (from-to)115054-115067
Number of pages14
Publication statusPublished - 2017

    Research areas

  • Androgen receptor, Castration resistant prostate cancer, DNA methylation, Prostate cancer, YAP1

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