Transcription factor KLLN inhibits tumor growth by AR suppression, induces apoptosis by TP53/TP73 stimulation in prostate carcinomas, and correlates with cellular differentiation

J Clin Endocrinol Metab. 2013 Mar;98(3):E586-94. doi: 10.1210/jc.2012-3490. Epub 2013 Feb 5.

Abstract

Context: KLLN is a newly identified gene with unknown function and shares a bidirectional promoter with PTEN.

Objective: The objective of the study was to analyze the relationship between KILLIN (KLLN) expression and prostate cancer and the potential tumor suppressive effect.

Design: We conducted an in silico analysis to compare KLLN expression in normal prostate and matched primary carcinoma tissues. We subsequently used immunohistochemistry to examine KLLN expression and association with Gleason grade and score in 109 prostatectomy samples. KLLN's tumor-suppressive effect was studied in androgen-dependent and androgen-independent cell models.

Patients: Patients were diagnosed with peripheral zone prostate carcinomas without metastasis at the time of prostatectomy. Each patient's primary tumor comprised at least 2 tumoral regions with different Gleason grades.

Results: KLLN expression decreased from normal prostate tissue to primary carcinomas (P < .0001). The loss of epithelial and stromal KLLN expression is associated with poor differentiation and high Gleason scores (P < .0001), consistent with our in vitro observation that KLLN inhibits tumor cell proliferation and invasiveness. KLLN decreases prostate-specific antigen levels and suppresses androgen-mediated cell growth by inhibiting androgen receptor (AR) transcription. As an androgen receptor-regulated target, KLLN also functions as a transcriptional activator, directly promoting the expression of TP53 and TP73, with consequent elevated apoptosis, regardless of AR status.

Conclusions: Our observations suggest that KLLN is a transcription factor directly regulating AR, TP53, and TP73 expression, with a role in prostate carcinogenesis. Loss of KLLN associates with high Gleason scores, suggesting that KLLN might be used as a potential prognostic marker for risk management and as a novel therapy target for advanced prostate carcinomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Apoptosis / physiology
  • Cell Differentiation / physiology
  • Cell Proliferation
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Humans
  • Male
  • Middle Aged
  • Models, Genetic
  • Neoplasm Grading
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Prognosis
  • Promoter Regions, Genetic / physiology
  • Prostate / pathology
  • Prostate / physiology
  • Prostatic Neoplasms / epidemiology
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology*
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism
  • Risk Factors
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • Nuclear Proteins
  • Receptors, Androgen
  • TP53 protein, human
  • TP73 protein, human
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • killin protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, human