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      Posttranslational regulation of androgen dependent and independent androgen receptor activities in prostate cancer

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          Abstract

          Prostate cancer (PCa) is the most commonly diagnosed cancer among men in western countries. Androgen receptor (AR) signaling plays key roles in the development of PCa. Androgen deprivation therapy (ADT) remains the standard therapy for advanced PCa. In addition to its ligand androgen, accumulating evidence indicates that posttranscriptional modification is another important mechanism to regulate AR activities during the progression of PCa, especially in castration resistant prostate cancer (CRPC). To date, a number of posttranscriptional modifications of AR have been identified, including phosphorylation ( e.g. by CDK1), acetylation ( e.g. by p300 and recognized by BRD4), methylation ( e.g. by EZH2), ubiquitination ( e.g. by SPOP), and SUMOylation ( e.g. by PIAS1). These modifications are essential for the maintenance of protein stability, nuclear localization and transcriptional activity of AR. This review summarizes posttranslational modifications that influence androgen-dependent and -independent activities of AR, PCa progression and therapy resistance. We further emphasize that in addition to androgen, posttranslational modification is another important way to regulate AR activity, suggesting that targeting AR posttranslational modifications, such as proteolysis targeting chimeras (PROTACs) of AR, represents a potential and promising alternate for effective treatment of CRPC. Potential areas to be investigated in the future in the field of AR posttranslational modifications are also discussed.

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          Most cited references116

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          Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.

          The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF complex for ubiquitination and degradation. To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds the angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting chimeric molecule 1 (Protac-1), was synthesized to recruit MetAP-2 to SCF. One domain of Protac-1 contains the I kappa B alpha phosphopeptide that is recognized by the F-box protein beta-TRCP, whereas the other domain is composed of ovalicin. We show that MetAP-2 can be tethered to SCF(beta-TRCP), ubiquitinated, and degraded in a Protac-1-dependent manner. In the future, this approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.
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            Catalytic in vivo protein knockdown by small-molecule PROTACs.

            The current predominant therapeutic paradigm is based on maximizing drug-receptor occupancy to achieve clinical benefit. This strategy, however, generally requires excessive drug concentrations to ensure sufficient occupancy, often leading to adverse side effects. Here, we describe major improvements to the proteolysis targeting chimeras (PROTACs) method, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target's ubiquitination and degradation. These compounds behave catalytically in their ability to induce the ubiquitination of super-stoichiometric quantities of proteins, providing efficacy that is not limited by equilibrium occupancy. We present two PROTACs that are capable of specifically reducing protein levels by >90% at nanomolar concentrations. In addition, mouse studies indicate that they provide broad tissue distribution and knockdown of the targeted protein in tumor xenografts. Together, these data demonstrate a protein knockdown system combining many of the favorable properties of small-molecule agents with the potent protein knockdown of RNAi and CRISPR.
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              EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent.

              Epigenetic regulators represent a promising new class of therapeutic targets for cancer. Enhancer of zeste homolog 2 (EZH2), a subunit of Polycomb repressive complex 2 (PRC2), silences gene expression via its histone methyltransferase activity. We found that the oncogenic function of EZH2 in cells of castration-resistant prostate cancer is independent of its role as a transcriptional repressor. Instead, it involves the ability of EZH2 to act as a coactivator for critical transcription factors including the androgen receptor. This functional switch is dependent on phosphorylation of EZH2 and requires an intact methyltransferase domain. Hence, targeting the non-PRC2 function of EZH2 may have therapeutic efficacy for treating metastatic, hormone-refractory prostate cancer.
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                Author and article information

                Contributors
                Journal
                Asian J Urol
                Asian Journal of Urology
                Second Military Medical University
                2214-3882
                2214-3890
                20 November 2019
                July 2020
                20 November 2019
                : 7
                : 3
                : 203-218
                Affiliations
                [a ]Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin Medical University, Tianjin, China
                [b ]Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, USA
                [c ]Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, USA
                [d ]Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, Rochester, USA
                Author notes
                []Corresponding author. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, USA. Huang.Haojie@ 123456mayo.edu
                [∗∗ ]Corresponding author. niuyuanjie@ 123456gmail.com
                Article
                S2214-3882(19)30111-0
                10.1016/j.ajur.2019.11.001
                7525085
                33024699
                921c450f-fe71-472b-8633-ac1cb183be91
                © 2020 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 2 April 2019
                : 21 August 2019
                : 11 October 2019
                Categories
                Review

                androgen receptor,posttranslational modification,phosphorylation,acetylation,methylation,ubiquitination,sumoylation,protac,spop,prostate cancer

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