A novel androgen receptor-binding element modulates Cdc6 transcription in prostate cancer cells during cell-cycle progression.
The androgen receptor (AR) plays a pivotal role in the onset and progression of prostate cancer by promoting cellular proliferation. Recent studies suggest AR is a master regulator of G1-S progression and possibly a licensing factor for DNA replication yet the mechanisms remain poorly defined. Here we report that AR targets the human Cdc6 gene for transcriptional regulation. Cdc6 is an essential regulator of DNA replication in eukaryotic cells and its mRNA expression is inversely modulated by androgen or antiandrogen treatment in androgen-sensitive prostate cancer cells. AR binds at a distinct androgen-response element (ARE) in the Cdc6 promoter that is functionally required for androgen-dependent Cdc6 transcription. We found that peak AR occupancy at the novel ARE occurs during the G1/S phase concomitant with peak Cdc6 mRNA expression. We also identified several of the coactivators and corepressors involved in AR-dependent Cdc6 transcriptional regulation in vivo and further characterized ligand-induced alterations in histone acetylation and methylation at the Cdc6 promoter. Significantly, AR silencing in prostate cancer cells markedly decreases Cdc6 expression and androgen-dependent cellular proliferation. Collectively, our results suggest that Cdc6 is a key regulatory target for AR and provide new insights into the mechanisms of prostate cancer cell proliferation.
Jin
Feng
F
Department of Physiology and Biophysics, Robert Wood Johnson Medical School, UMDNJ, Piscataway, NJ 08854, USA.
Fondell
Joseph D
JD
D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009570:Nitriles / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D014105:Tosyl Compounds / Q000494:pharmacology; D015533:Transcriptional Activation
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D006657:Histones; D009570:Nitriles; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide