Androgen receptor overexpression in prostate cancer linked to Pur alpha loss from a novel repressor complex.
Increased androgen receptor (AR) expression and activity are pivotal for androgen-independent (AI) prostate cancer (PC) progression and resistance to androgen-deprivation therapy. We show that a novel transcriptional repressor complex that binds a specific sequence (repressor element) in the AR gene 5'-untranslated region contains Pur alpha and hnRNP-K. Pur alpha expression, its nuclear localization, and its AR promoter association, as determined by chromatin immunoprecipitation analysis, were found to be significantly diminished in AI-LNCaP cells and in hormone-refractory human PCs. Transfection of AI cells with a plasmid that restored Pur alpha expression reduced AR at the transcription and protein levels. Pur alpha knockdown in androgen-dependent cells yielded higher AR and reduced p21, a gene previously shown to be under negative control of AR. These changes were linked to increased proliferation in androgen-depleted conditions. Treatment of AI cells with histone deacetylase and DNA methylation inhibitors restored Pur alpha protein and binding to the AR repressor element. This correlated with decreased AR mRNA and protein levels and inhibition of cell growth. Pur alpha is therefore a key repressor of AR transcription and its loss from the transcriptional repressor complex is a determinant of AR overexpression and AI progression of PC. The success in restoring Pur alpha and the repressor complex function by pharmacologic intervention opens a promising new therapeutic approach for advanced PC.
Wang
Longgui G
LG
New York University Cancer Institute, New York, New York 10016, USA.
Johnson
Edward M
EM
Kinoshita
Yayoi
Y
Babb
James S
JS
Buckley
Michael T
MT
Liebes
Leonard F
LF
Melamed
Jonathan
J
Liu
Xiao-Mei
XM
Kurek
Ralf
R
Ossowski
Liliana
L
Ferrari
Anna C
AC
D020121:5' Untranslated Regions / Q000235:genetics; D045744:Cell Line, Tumor; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases / Q000235:genetics; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
D020121:5' Untranslated Regions; D017931:DNA Primers; D004268:DNA-Binding Proteins; C501130:PURA protein, human; D011944:Receptors, Androgen; D012097:Repressor Proteins; D014157:Transcription Factors; D008156:Luciferases