PLZF regulates Pbx1 transcription and Pbx1-HoxC8 complex leads to androgen-independent prostate cancer proliferation.
BACKGROUND
Promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor and negative regulator of the cell cycle, has been characterized as a prostatic androgen-responsive gene. DU145 cells show androgen-independent growth and lack PLZF gene expression.


METHODS
We analyzed PLZF-regulating genes by DNA microarray using DU145 cells infected with LacZ- or PLZF-carrying adenoviruses.


RESULTS
DNA microarray revealed that Pbx1 is a prominent suppressed gene in PLZF-overexpressing DU145 cells. Androgen receptor (AR)-expressing DU145 cells recovered androgen-dependent PLZF expression and subsequent repression of Pbx1 expression. Immunoprecipitation of Pbx1 in DU145 cells revealed a Pbx1-HoxC8 heterocomplex. siRNAs for Pbx1 and HoxC8 knocked downexpression of each, and this suppressed androgen-independent cell growth. Double knockdown of both Pbx1 and HoxC8 suppressed cell growth much more significantly.


CONCLUSIONS
Androgen-independent cell line DU145 cells lack PLZF gene expression, resulting in the upregulation of Pbx1 and HoxC8 expression. The Pbx1-HoxC8 heterocomplex may lead to androgen-independent growth in prostate cancer.
Kikugawa
Tadahiko
T
Department of Biochemistry and Molecular Genetics, Ehime University School of Medicine, Shitsukawa, To-on, Ehime, Japan.
Kinugasa
Yumi
Y
Shiraishi
Ken
K
Nanba
Daisuke
D
Nakashiro
Koh-ichi
K
Tanji
Nozomu
N
Yokoyama
Masayoshi
M
Higashiyama
Shigeki
S
D000728:Androgens / Q000502:physiology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection
D000728:Androgens; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C489815:HOXC8 protein, human; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C083400:PBX1 protein, human; C092037:ZBTB16 protein, human