Deacetylation of Androgen Receptor by SIRT2 and its Dysregulation Promotes Pathogenesis and Progression of Prostate Cancer

Abstract

Aim: The purpose of the study was to investigate whether the androgen receptor (AR) whose activity is closely associated with prostate cancer is post-translationally regulated by a NAD+ dependent and aging associated protein, sirtuin2 (SIRT2). Material and Method: Immunoprecipitation-Western blotting was conducted to examine the association of the AR and SIRT2 in cultured 293T and LNCaP cells. In addition, we performed in vitro deacetylation assays using purified SIRT2 and AR proteins. Results: SIRT2 gene removal mouse prostate had hyper-acetylated the AR. In vitro and in vivo interaction assays revealed that SIRT2 physically interacted with the AR in prostate cancer cell line LNCaP. Finally, SIRT2 deacetylated the AR in vitro conditions. Conclusion: SIRT2 interacted with the AR and deacetylated it. Identifying partners of the AR and molecular mechanisms of its regulation is curial for understanding the pathogenesis of prostate cancer. Using small molecules to activate SIRT2 might be an important clinical approach to prevent, treat or delay the prostate cancer progression.

Keywords

• prostate; cancer; post-translational regulation; sirtuin; deacetylation

Androjen Reseptörünün SIRT2 ile Diasetilasyonu ve Bundaki Eksiklik Prostat Kanseri Patojenite ve İlerlemesini Uyarır

Abstract

Amaç: Bu çalışmanın amacı, aktivitesi prostat kanseriyle yakın ilişkili olan androjen reseptörünün (AR), NAD+’ye bağımlı ve yaşlanmayla alakalı bir protein olan sirtuin2 (SIRT2) tarafından posttranslasyonel olarak düzenlenmesini araştırmaktır. 
Materyal ve Metot: İmmunolojik çökeltme-Western blot teknikleriyle AR ve SIRT2 arasındaki etkileşim 293T ve LNCaP hücre kültürlerinde incelenmiştir. İlaveten, saflaştırılmış SIRT2 ve AR proteinleriyle in vitro diasetilasyon çalışmaları yapılmıştır. 
Bulgular: SIRT2 geni uzaklaştırılmış farenin prostatındaki AR aşırı derecede asetile edildi. İn vitro ve in vivo etkileşim deneyleri SIRT2’nin AR’la fiziksel etkileşim gösterdiğini ortaya çıkarttı. Son olarak, SIRT2, AR’ı in vitro koşullarda diasetile etti. 
Sonuç: SIRT2, AR ile etkileşim kurup onu diasetile etti. AR’a bağlanan diğer proteinler ve onun düzenlenmesinin moleküler mekanizmasını tanımlamak, prostat kanserinin patojenitesini anlamak açısından büyük bir öneme sahiptir. SIRT2’yi küçük moleküller aracılıyla aktive etmek prostat kanserinin engelleme, tedavi etme veya gelişimini yavaşlatmak açısından klinik öneme sahip olabilir.

Keywords

• prostat,kanser,post-translasyonel düzenleme; sirtuin; diasetilasyon

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