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

doi:10.1016/j.ajur.2019.11.001

Asian Journal of Urology, 2020, 7 (3): 203-218 doi: 10.1016/j.ajur.2019.11.001

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

Simeng Wen^a,b,Yuanjie Niu^a,**(

),Haojie Huang^b,c,d,*(

)

^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

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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.

Key words： Androgen receptor Posttranslational modification Phosphorylation Acetylation Methylation Ubiquitination SUMOylation PROTAC SPOP Prostate cancer

Received: 02 April 2019 Available online: 20 July 2020

Corresponding Authors: Yuanjie Niu,Haojie Huang E-mail: niuyuanjie@gmail.com;Huang.Haojie@mayo.edu

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Simeng Wen,Yuanjie Niu,Haojie Huang. Posttranslational regulation of androgen dependent and independent androgen receptor activities in prostate cancer[J]. Asian Journal of Urology, 2020, 7(3): 203-218.

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http://www.ajurology.com/EN/10.1016/j.ajur.2019.11.001 OR http://www.ajurology.com/EN/Y2020/V7/I3/203

A diagram summarizing posttranslational modifications of the AR. Residues on AR that are known to be modulated by posttranslational modifications, including phosphorylation (P), acetylation (A), methylation (M), ubiquitination (U) and SUMOylation (S) are listed. Modifications of phosphorylation, acetylation and methylation with a positive effect on AR transcriptional activity are highlighted in red color whereas those with a negative effect were colored in green. Some modifications have dual functions, while the functions of some modifications remain unclear. An asterisk indicates p300 does not function as a kinase for S81 phosphorylation, but instead acts as a “reader” that can bind to this phosphorylated site. AR, androgen receptor; NTD, N-terminal domain; DBD, DNA-binding domain; LBD, ligand-binding domain.

Phosphorylation residues of AR.

Acetylation residues of AR.

Methylation residues of AR.

Scheme of AR Ub. Ub is catalyzed by several enzymes, including the E1, E2, and E3. Once the protein substrate is tagged with ubiquitin through the lysine48-linked polyubiquitination, it is recognized by the proteasome for degradation. AR, androgen receptor; Ub, ubiquitin; ATP, adenosine-triphosphate; E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzymes; E3, ubiquitin ligases; DBD, DNA-binding domain.

Ubiquitination residues of AR.

SUMOylation residues of AR.

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