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

Oncogene. 2021 Apr;40(13):2407-2421. doi: 10.1038/s41388-021-01718-4. Epub 2021 Mar 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Aged
  • Animals
  • Benzamides / administration & dosage*
  • Benzamides / adverse effects
  • COUP Transcription Factor II / genetics*
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heterografts
  • Humans
  • Lipid Metabolism / drug effects
  • Male
  • Mice
  • MicroRNAs / genetics*
  • Middle Aged
  • Neoplastic Stem Cells / drug effects
  • Nitriles / administration & dosage*
  • Nitriles / adverse effects
  • Phenylthiohydantoin / administration & dosage*
  • Phenylthiohydantoin / adverse effects
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Transcription Factors / genetics*
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Benzamides
  • COUP Transcription Factor II
  • MIRN21 microRNA, human
  • MicroRNAs
  • NR2F2 protein, human
  • Nitriles
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Phenylthiohydantoin
  • enzalutamide