| Gene information | Literature | Expression | lncRNA | Mutation | Homolog |
Basic Information | |
|---|---|
Gene ID | 990 |
Name | CDC6 |
Synonymous | cell division cycle 6;CDC6;cell division cycle 6 |
Definition | CDC6 cell division cycle 6 homolog|CDC6-related protein|cdc18-related protein|cell division control protein 6 homolog|cell division cycle 6 homolog|p62(cdc6) |
Position | 17q21.3 |
Gene type | protein-coding |
Title | Abstract |
| Oncogenic activity of Cdc6 through repression of the INK4/ARF locus. | The INK4/ARF locus encodes three tumour suppressors (p15(INK4b), ARF and p16(INK4a)) and is among the most frequently inactivated loci in human cancer. However, little is known about the mechanisms that govern the expression of this locus. Here we have identified a putative DNA replication origin at the INK4/ARF locus that assembles a multiprotein complex containing Cdc6, Orc2 and MCMs, and that coincides with a conserved noncoding DNA element (regulatory domain RD(INK4/ARF)). Targeted and localized RNA-interference-induced heterochromatinization of RD(INK4/ARF) results in transcriptional repression of the locus, revealing that RD(INK4/ARF) is a relevant transcriptional regulatory element. Cdc6 is overexpressed in human cancers, where it might have roles in addition to DNA replication. We have found that high levels of Cdc6 result in RD(INK4/ARF)-dependent transcriptional repression, recruitment of histone deacetylases and heterochromatinization of the INK4/ARF locus, and a concomitant decrease in the expression of the three tumour suppressors encoded by this locus. This mechanism is reminiscent of the silencing of the mating-type HM loci in yeast by replication factors. Consistent with its ability to repress the INK4/ARF locus, Cdc6 has cellular immortalization activity and neoplastic transformation capacity in cooperation with oncogenic Ras. Furthermore, human lung carcinomas with high levels of Cdc6 are associated with low levels of p16(INK4a). We conclude that aberrant expression of Cdc6 is oncogenic by directly repressing the INK4/ARF locus through the RD(INK4/ARF) element. |
| FOXM1 and androgen receptor co-regulate CDC6 gene transcription and DNA replication in prostate cancer cells. | 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. |