Transcription Factor KLLN Inhibits Tumor Growth by AR Suppression, Induces Apoptosis by TP53/TP73 Stimulation in Prostate Carcinomas, and Correlates With Cellular Differentiation

Journal of Clinical Endocrinology and Metabolism

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 andTP73, with consequent elevated apoptosis, regardless of AR status.

CONCLUSIONS
Our observations suggest that KLLN is a transcription factor directly regulating ARTP53, 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.