The e3 ubiquitin ligase siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity.
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: The Siah1 and Siah2 E3 ubiquitin ligases play an important role in diverse signaling pathways and have been shown to be deregulated in cancer. The human Siah1 and Siah2 isoforms share high sequence similarity but possess contrary roles in cancer, with Siah1 more often acting as a tumor suppressor while Siah2 functions as a proto-oncogene. The different function of Siah1 and Siah2 in cancer is likely due to the ubiquitination of distinct substrates. Hence, we decided to investigate the molecular basis of the substrate specificity, utilizing the well-characterized Siah2 substrate PHD3. Using chimeric and mutational approaches, we identified critical residues in Siah2 that promote substrate specificity. Thus, we have found that four residues in the N-terminal region of the Siah2 substrate binding domain (SBD) (Ser132, His150, Pro155, Tyr163) are critical for substrate specificity. In the C-terminal region of the SBD, a single residue, Leu250, was identified to promote the specific binding of Siah2 SBD to PHD3. Our study may help to overcome the challenges in the identification of Siah2 specific inhibitors.PLoS ONE 09/2014; 9(9):e106547. · 3.53 Impact Factor
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ABSTRACT: Prostate cancer co-opts a unique set of cellular pathways in its initiation and progression. The heterogeneity of prostate cancers is evident at earlier stages, and has led to rigorous efforts to stratify the localized prostate cancers, so that progression to advanced stages could be predicted based upon salient features of the early disease. The deregulated androgen receptor signaling is undeniably most important in the progression of the majority of prostate tumors. It is perhaps because of the primacy of the androgen receptor governed transcriptional program in prostate epithelium cells that once this program is corrupted, the consequences of the ensuing changes in activity are pleotropic and could contribute to malignancy in multiple ways. Following localized surgical and radiation therapies, 20-40% of patients will relapse and progress, and will be treated with androgen deprivation therapies. The successful development of the new agents that inhibit androgen signaling has changed the progression free survival in hormone resistant disease, but this has not changed the almost ubiquitous development of truly resistant phenotypes in advanced prostate cancer. This review summarizes the current understanding of the molecular pathways involved in localized and metastatic prostate cancer, with an emphasis on the clinical implications of the new knowledge.Oncotarget 09/2014; 5(17):7217-59. · 6.63 Impact Factor
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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 (). 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.Receptors & clinical investigation. 01/2014; 1(5).
The E3 Ubiquitin Ligase Siah2 Contributes to
Castration-Resistant Prostate Cancer by Regulation
of Androgen Receptor Transcriptional Activity
Jianfei Qi,* Manisha Tripathi, Rajeev Mishra, Natasha Sahgal, Ladan Fazli, Susan Ettinger, William J. Placzek,
Giuseppina Claps, Leland W.K. Chung, David Bowtell, Martin Gleave, Neil Bhowmick, and Ze’ev A. Ronai*
*Correspondence: email@example.com (J.Q.), firstname.lastname@example.org (Z.A.R.)
(Cancer Cell 23, 332–346; March 18, 2013)
Dr. Laden Fazli’s name was spelled incorrectly as ‘‘Fazil’’ in the original article. It appears correctly in this erratum.
Cancer Cell 23, 853, June 10, 2013 ª2013 Elsevier Inc. 853