Abstract
BackgroundAbnormal reactivation of androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) mainly results from overexpression and down-regulation of AR. Sumoylation of AR can influence its function. However, regulation of AR sumoylation by SUMO E3 ligases PIASs to modify AR distribution and stability are not well understood.MethodsWe assessed the potential effect of SUMO3 modification on AR intracellular localization by immunostaining in AR-negative prostate cancer DU145 cells, and detected the effect of PIAS1/SUMO3 overexpression on AR sumoylation related degradation. Then we characterized AR sumoylation sites involved modified by SUMO3, and the key residue of PIAS1 involved in itself sumoylation and further mediated AR sumoylation (sumo3-conjugated), translocation and degradation. Finally we detected the recognition of PIAS1 (sumoylation ligase) to MDM2, a ubiquin ligase mediated AR degradation.ResultsWe demonstrate that SUMO E3 ligase PIAS1, along with SUMO3, mediates AR cytosolic translocation and subsequent degradation via a ubiquitin-proteasome pathway. Although AR sumoylation occurs prior to ubiquitination, the SUMO-acceptor lysine 386 on AR, together with ubiquitin-acceptor lysine 845, contribute to PIAS1/SUMO3-induced AR nuclear export, ubiquitination and subsequent degradation. Moreover, PIAS1 itself is modified by SUMO3 overexpression, and mutation of SUMO-acceptor lysine 117 on PIAS1 can impair AR cytoplasmic distribution, demonstrating the essential role of sumoylated PIAS1 in AR translocation. We further determine that sumoylated PIAS1 interacts with AR lysine 386 and 845 to form a binary complex. Consistent with the effect on AR distribution, SUMO3 modification of PIAS1 is also required for AR ubiquitination and degradation by recruiting ubiquitin E3 ligase MDM2.ConclusionTaken together, SUMO3 modification of PIAS1 modulates AR cellular distribution and stability. Our study provided the evidence the crosstalk between AR sumoylation and ubquitination mediated by PIAS1 and SUMO3.
Highlights
Abnormal reactivation of androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) mainly results from overexpression and down-regulation of AR
We explore a crosstalk mechanism between AR sumoylation and ubquitination We explored a crosstalk mechanism between AR sumoylation and ubquitination, which is mediated by PIAS1 and SUMO3
We discovered that SUMO3 modification by PIAS1 modulates AR cellular distribution and stability
Summary
Abnormal reactivation of androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) mainly results from overexpression and down-regulation of AR. In CRPC, AR signaling abnormally activates even at low androgen levels post-castration [4], and occurs via several mechanisms, including AR gene amplification and overexpression [5], abnormal AR stability regulation [6], AR mutations or splice variant [7, 8], altered expression of AR co-factors [9], or altered interactions between AR and cofactors, etc. Similar to other nuclear receptors, AR is subject to regulation by the ubiquitin-proteasome pathway [13], and some proteins, such as MDM2 or ChIP, can function as ubiquitin E3 ligases to ubiquinate AR [14,15,16]. The process of enzyme-mediated, small ubiquitin-related modifier (SUMO) protein conjugation is termed sumoylation. SUMO modification can regulate e.g. protein-protein or protein-DNA interactions, protein subcellular translocation, sub-nuclear structure formation, and protein stability [14, 18, 19]
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