title: FOXM1 and androgen receptor co-regulate CDC6 gene transcription and DNA replication in prostate cancer cells.
abstract: CDC6 is a key component of the DNA replication initiation machinery, and its transcription is regulated by E2F or androgen receptor (AR) alone or in combination in prostate cancer (PCa) cells. Through both overexpression and knockdown approaches, we found that in addition to its effects on the E2F pathway, the cell proliferation specific transcription factor FOXM1 stimulated CDC6 transcription in cooperation with AR. We have identified a forkhead box motif in the CDC6 proximal promoter that is occupied by FOXM1 and is sufficient to drive FOXM1-regulated transcription. Indirectly, FOXM1 elevated AR protein levels and AR dependent transcription. Furthermore, FOXM1 and AR proteins physically interact. Using synchronized cultures, we observed that CDC6 expression is elevated near S phase of the cell cycle, at a time coinciding with elevated FOXM1 and AR expression and CDC6 promoter occupancy by both AR and FOXM1 proteins. Androgen increased the binding of AR protein to CDC6 promoter, and AR and FOXM1 knockdown decreased AR binding. These results provided new evidence for the regulatory mechanism of aberrant CDC6 oncogene transcription by FOXM1 and AR, two highly expressed transcription factors in PCa cells. Functionally, the cooperation of FOXM1 and AR accelerated DNA synthesis and cell proliferation by affecting CDC6 gene expression. Furthermore, siomycin A, a proteasome inhibitor known to inhibit FOXM1 expression and activity, inhibited PCa cell proliferation and its effect was additive to that of bicalutamide, an antiandrogen commonly used to treat PCa patients.
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, People's Republic of China.
authors.forename: Youhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, People's Republic of China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, People's Republic of China.
authors.forename: Lunquan
authors.initials: L
authors.lastname: Sun
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, People's Republic of China. Electronic address: xiolijob@gmail.com.
authors.forename: Xiong
authors.initials: X
authors.lastname: Li
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004261:DNA Replication / Q000235:genetics; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010455:Peptides / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; D010455:Peptides; D011944:Receptors, Androgen; C024711:siomycin A
keywords: AR; DNA replication; FOXM1; Transcription factor; Transcription regulation