title: Transcription factor KLLN inhibits tumor growth by AR suppression, induces apoptosis by TP53/TP73 stimulation in prostate carcinomas, and correlates with cellular differentiation.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors: Yu
authors: Y
authors: Wang
authors: Deepa
authors: D
authors: Radhakrishnan
authors: Xin
authors: X
authors: He
authors: Donna M
authors: DM
authors: Peehl
authors: Charis
authors: C
authors: Eng
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000502:physiology; D011467:Prostate / Q000473:pathology / Q000502:physiology; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C554482:KLLN protein, human; D009687:Nuclear Proteins; D011944:Receptors, Androgen; C495901:TP53 protein, human; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
references: Clin Cancer Res. 2012 Mar 15;18(6):1578-87
references: 22275508
references: Am J Pathol. 2009 Aug;175(2):489-99
references: 19628766
references: Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5396-401
references: 18385383
references: J Biol Chem. 1993 Dec 15;268(35):26400-8
references: 8253765
references: Hum Mol Genet. 2010 Nov 15;19(22):4319-29
references: 20729295
references: Nat Med. 1999 Mar;5(3):280-5
references: 10086382
references: Endocr Rev. 1999 Feb;20(1):22-45
references: 10047972
references: Cancer Res. 2001 May 1;61(9):3550-5
references: 11325816
references: Clin Cancer Res. 2009 Jun 1;15(11):3842-9
references: 19435838
references: Nat Rev Cancer. 2001 Oct;1(1):34-45
references: 11900250
references: Biochem J. 2002 Sep 15;366(Pt 3):729-36
references: 11971763
references: BJU Int. 2005 Dec;96(9):1241-6
references: 16287438
references: Oncogene. 2011 Oct 20;30(42):4327-38
references: 21532617
references: Clin Invest Med. 1993 Dec;16(6):475-92
references: 8013153
references: Oncogene. 2008 Nov 27;27(56):7106-17
references: 18776922
references: Prostate. 2000 May 15;43(3):225-32
references: 10797498
references: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references: 19474385
references: J Urol. 1995 Aug;154(2 Pt 1):414-21
references: 7609105
references: JAMA. 2010 Dec 22;304(24):2724-31
references: 21177507
references: Nat Genet. 1995 Apr;9(4):401-6
references: 7795646
references: Nature. 1997 Sep 11;389(6647):191-4
references: 9296498
references: Urol Clin North Am. 1999 May;26(2):263-73
references: 10361549
references: Mol Endocrinol. 2004 Oct;18(10):2409-23
references: 15205473
references: N Engl J Med. 2011 May 26;364(21):1995-2005
references: 21612468
references: Cell. 1997 Aug 22;90(4):809-19
references: 9288759
references: Endocr Rev. 1999 Jun;20(3):321-44
references: 10368774
references: Mol Endocrinol. 1997 Jan;11(1):3-15
references: 8994183
references: Cancer Res. 2000 Feb 15;60(4):944-9
references: 10706109
references: Endocr Relat Cancer. 2005 Mar;12(1):119-34
references: 15788644
references: Cancer Res. 1994 Oct 15;54(20):5474-8
references: 7522959
references: Cancer Res. 1998 Dec 15;58(24):5718-24
references: 9865729
references: J Biol Chem. 2000 Aug 11;275(32):24500-5
references: 10827191
references: Oncogene. 2007 Sep 6;26(41):6061-70
references: 17420725
references: Curr Cancer Drug Targets. 2007 Sep;7(6):591-604
references: 17896924
references: Science. 2009 May 8;324(5928):787-90
references: 19359544
references: Clin Cancer Res. 1996 Feb;2(2):389-98
references: 9816182