The e3 ubiquitin ligase siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity.

Signal Transduction Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla 92037, CA, USA. Electronic address: .
Cancer cell (Impact Factor: 25.29). 03/2013; 23(3):332-46. DOI: 10.1016/j.ccr.2013.02.016
Source: PubMed

ABSTRACT Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development.

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    ABSTRACT: Prostate cancer (PCa) primarily depends on the dysregulations of androgen receptor (AR) signaling pathway for the initiation and growth as well as recurrence after chemotherapy ([1]). Androgen deprivation therapy (ADT) effectively alleviates symptoms of the malignancy to arrest further growth of primary tumors or progression of metastasis in patients with advanced PCa. However, relapse occurs in many patients after a short period, and PCa cells eventually become insensitive to ADT - termed castration resistant prostate cancer (CRPC) ([2, 3]). Tremendous advancements have been achieved to decipher the mechanisms on AR signaling, and the ubiquitination machinery contributes to PCa directly or indirectly by either promotion of AR transcriptional activity or degradation of AR protein levels. The recent report reveals that SKP2 regulates AR protein through ubiquitin-mediated proteasomal degradation, highlighting the role of SKP2 in AR signaling. Given the pivotal roles of AKT and SKP2 in cancers, the differential mechanisms of AR ubiquitination by various E3 ligases hold valuable significance and beneficial implications for PCa control.
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