Androgen regulates Cdc6 transcription through interactions between androgen receptor and E2F transcription factor in prostate cancer cells

Abstract

Androgen receptor plays a critical role in the development and maintenance of cancers in the prostate. Earlier, we have shown that Cdc6, a regulatory protein for initiation of DNA replication, is down regulated in androgen-insensitive prostate cancer cells. In this report, we studied the involvement of androgen, mediated through androgen receptor (AR) in regulation of Cdc6 expression. Our results demonstrated that androgen treatment stimulated Cdc6 expression in xenograft tumors and androgen-sensitive prostate cancer cells. We also showed that androgen treatment stimulated Cdc6 transcription through possible interaction of AR with the ARE sequence in the Cdc6 promoter and that the stimulatory effect of androgen required intact E2F binding sites in the promoter. Androgen treatment differentially altered nuclear availability of E2F1 and E2F3, and increased the amount of hypophosphorylated retinoblastoma protein (pRb) in the nucleus in a time dependent fashion. We further showed that AR interacted with E2F transcription factors in a ligand-independent manner and that ligand-bound AR was less efficient in interacting with E2F proteins. DNA-protein interaction assays indicated that androgen treatment altered binding of E2F1 to the Cdc6 promoter in prostate cancer cells. We conclude that AR regulates Cdc6 transcription through interaction with the Cdc6 promoter, and complex formation with E2F1 and E2F3 in a differential manner.

Juvenile Hormone Activates the Transcription of Cell-division-cycle 6 (Cdc6) for Polyploidy-dependent Insect Vitellogenesis and Oogenesis

“…Androgen can act through its receptor binding to a 15-bp palindromic androgen response element in the Cdc6 promoter on the transcription of Cdc6 gene in prostate cancer cells (55,68). By qRT-PCR, we showed that Cdc6 expression was significantly increased in the fat body and ovary post adult female eclosion, which are in conformity with the elevated JH titers (50,51).…”

Integrative Analysis Reveals the Transcriptional Collaboration between EZH2 and E2F1 in the Regulation of Cancer-Related Gene Expression

“…Although the androgen response element (ARE) is not listed among the top transcription factor binding motifs enriched in EZH2 ChIP-seq dataset, we confirmed its significant enrichment in the proximal region of EZH2 solo peaks. It is interesting to note that the Rb/E2F1 pathway has been shown as a critical regulator of AR expression and transcriptional activity (42-44). Although the activator E2Fs are generally believed to have a great deal of functional redundancy, only E2F1 and E2F3 were shown to enhance AR activity, while E2F2 was insufficient for this function (42).…”

Proto-oncogene Activity of Melanoma Antigen-A11 (MAGE-A11) Regulates Retinoblastoma-related p107 and E2F1 Proteins

“…A threshold model was proposed where genes that regulate cell proliferation or apoptosis are induced by different levels of E2F that act as positive or negative regulators of cell growth (53). Positive and negative cooperation in gene regulation by AR and E2F1 were reported in prostate cancer cells (95)(96)(97). Relative levels of MAGE-A11 and p107 influence AR and E2F1 transcriptional activation or repression.…”