YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer

Hsiu Chi Lee, Chien Hui Ou, Yun Chen Huang, Pei Chi Hou, Chad J. Creighton, Yi Syuan Lin, Che Yuan Hu, Shih Chieh Lin

研究成果: Article同行評審

4 引文 斯高帕斯(Scopus)

摘要

Metastatic castration-resistant prostate cancer (mCRPC) is a malignant and lethal disease caused by relapse after androgen-deprivation (ADT) therapy. Since enzalutamide is innovated and approved by US FDA as a new treatment option for mCRPC patients, drug resistance for enzalutamide is a critical issue during clinical usage. Although several underlying mechanisms causing enzalutamide resistance were previously identified, most of them revealed that drug resistant cells are still highly addicted to androgen and AR functions. Due to the numerous physical functions of AR in men, innovated AR-independent therapy might alleviate enzalutamide resistance and prevent production of adverse side effects. Here, we have identified that yes-associated protein 1 (YAP1) is overexpressed in enzalutamide-resistant (EnzaR) cells. Furthermore, enzalutamide-induced YAP1 expression is mediated through the function of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) at the transcriptional and the post-transcriptional levels. Functional analyses reveal that YAP1 positively regulates numerous genes related to cancer stemness and lipid metabolism and interacts with COUP-TFII to form a transcriptional complex. More importantly, YAP1 inhibitor attenuates the growth and cancer stemness of EnzaR cells in vitro and in vivo. Finally, YAP1, COUP-TFII, and miR-21 are detected in the extracellular vesicles (EVs) isolated from EnzaR cells and sera of patients. In addition, treatment with EnzaR-EVs induces the abilities of cancer stemness, lipid metabolism and enzalutamide resistance in its parental cells. Taken together, these results suggest that YAP1 might be a crucial factor involved in the development of enzalutamide resistance and can be an alternative therapeutic target in prostate cancer.

原文English
頁(從 - 到)2407-2421
頁數15
期刊Oncogene
40
發行號13
DOIs
出版狀態Published - 2021 四月 1

All Science Journal Classification (ASJC) codes

  • 分子生物學
  • 遺傳學
  • 癌症研究

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