Up regulation of the Hippo signalling effector YAP1 is linked to early biochemical recurrence in prostate cancers

Sci Rep. 2020 Jun 2;10(1):8916. doi: 10.1038/s41598-020-65772-w.

Abstract

The transcriptional coactivator YAP1 controls the balance between cell proliferation and apoptosis. YAP1 overexpression is linked to poor prognosis in many cancer types, yet its role in prostate cancer is unknown. Here, we applied YAP1 immunohistochemistry to a tissue microarray containing 17,747 clinical prostate cancer specimens. Cytoplasmic and nuclear YAP1 staining was seen in 81% and 63% of tumours. For both cytoplasmic and nuclear YAP1 staining, high levels were associated with advanced tumour stage, classical and quantitative Gleason grade, positive nodal stage, positive surgical margin, high KI67 labelling index, and early biochemical recurrence (p < 0.0001 each). The prognostic role of YAP1 staining was independent of established prognostic features in multivariate models (p < 0.001). Comparison with previously studied molecular markers identified associations between high YAP1 staining, TMPRSS2:ERG fusion (p < 0.0001), high androgen receptor (AR) expression (p < 0.0001), high Ki67 labelling index (p < 0.0001), and PTEN and 8p deletions (p < 0.0001 each). In conclusion, high YAP1 protein expression is an independent predictor of unfavourable disease course in prostate cancer. That cytoplasmic and nuclear YAP1 staining is equally linked to phenotype and prognosis fits well to a model where YAP1 activation during tumour progression includes up regulation, cytoplasmic accumulation and subsequent translocation to the nucleus.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Aged
  • Apoptosis
  • Cell Proliferation
  • Hippo Signaling Pathway
  • Humans
  • Ki-67 Antigen / metabolism
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / metabolism*
  • Neoplasm Recurrence, Local / pathology
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Serine-Threonine Kinases / metabolism*
  • Receptors, Androgen / metabolism
  • Tissue Array Analysis
  • Transcription Factors / metabolism*
  • Up-Regulation
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Ki-67 Antigen
  • MKI67 protein, human
  • Receptors, Androgen
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Protein Serine-Threonine Kinases