Cyclin D3 action in androgen receptor regulation and prostate cancer

Abstract

Prostate cancer (PCa) cell proliferation is dependent on activation of the androgen receptor (AR), a liganddependent transcription factor. AR activation controls G1-S phase progression through fostering enhanced translation of the D-type cyclins, which promote cell cycle progression through activation of CDK4/6. However, the D-type cyclins harbor additional, CDK4/6 kinase-independent, functions through manipulation of transcription factors, including AR. It was previously established that cyclins D1 and D3 have the potential to modulate AR, and with regard to cyclin D1, disruption of this function occurs in human tumors. Therefore, it was essential to interrogate cyclin D3 function in this tumor type. Here, we show that cyclin D3 is found in association with AR in PCa cells, as mediated through a conserved motif. Cyclin D3 functions to attenuate AR activity through defined mechanisms that include modulation of ligand-dependent conformational changes and modulation of chromatin binding activity. Accumulated cyclin D3 slows cell proliferation in AR-dependent cells, thus suggesting that androgen-induced D-type cyclin production serves to temper the mitogenic response to androgen. Supporting this hypothesis, it is shown that cyclin D3 expression is reduced in primary PCas as a function of tumor grade, and inversely correlates with the proliferative index. In total, these data identify cyclin D3 as a critical modulator of the androgen response, whose deregulation may foster unchecked AR activity in PCa.

Expression, regulation and function of the ISGylation system in prostate cancer

“…AR activity is modulated by different signal-transduction pathways (Reddy et al, 2006), by cyclins (Olshavsky et al, 2008), by interaction with numerous co-activators and repressors (Heemers and Tindall, 2007) and by diverse posttranslational modifications, including the covalent conjugation of the small ubiquitin-like protein, SUMO-1 (Callewaert et al, 2004). In addition, mutations preferentially occurring in the ligand-binding domain of AR in advanced PCa modify ligand specificity, thereby decreasing the dependence on androgens for the stimulation of proliferation (Taplin and Balk, 2004).…”

Caspase-2-Based Regulation of the Androgen Receptor and Cell Cycle in the Prostate Cancer Cell Line LNCaP

“…23 Cyclin D3 is also linked to attenuation of the ligand-dependent proliferation-promoting function of AR in AR-dependent prostate cancer cells. 18 Zong et al demonstrated a potential CDK4-independent mechanism for cyclin D3-mediated repression of both AR-dependent transcriptional activity and AR-dependent proliferation, whereby a cyclin D3/AR complex that also incorporates CDK11p58 induces AR phosphorylation at Ser-308. 39,40 We found that in contrast to cyclin D3 expression, the downregulation of caspase-2 expression inhibits AR activity in LNCaP cells (Fig.…”

“…Recently, Olshavsky et al 18 found that cyclin D3 immunoprecipitates with AR in prostate cancer cells. Cyclin D3 inhibits AR activity by modulating ligand-dependent conformational changes and chromatin binding activity.…”

“…Cyclin D3-mediated AR repression requires an association with HDAC3; inhibition of HDAC3 activity using the histone deacetylase inhibitor (HDI) TSA abrogates cyclin D3 repression. 18 Immunoprecipitation analysis of caspase-2 and anti-p21/ Cip1 indicates that TSA treatment promotes the formation of complexes that incorporate caspase-2, cyclin D3, and p21/Cip1 (Fig. 5A).…”

“…[16][17][18] This inhibition is independent of CDK and thus is also independent of the role of cyclins D1 and D3 in Rb phosphorylation. 16,18 Regulation of G1 CDK activity is affected by the association of CDKs with inhibitory proteins (CKIs) that can either physically block activation or block substrate/ATP access. 19 The known CKIs are grouped into two gene families, Ink4 and Cip/Kip, according to structural similarities.…”