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

Yıl 2017, , 97 - 101, 01.08.2017

Özkan Özden

https://doi.org/10.5505/kjms.2017.17894

Öz

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.

Anahtar Kelimeler

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

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

Öz

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.

Anahtar Kelimeler

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

Kaynakça

• 1. SEER Cancer Statistics Factsheets: Prostate Cancer. National Cancer Institute. Bethesda, MD. Available at: http://seer.cancer. gov/statfacts/html/prost.html (Accessed: 24th March 2016).
• 2. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nature Med 2004;10:33–9.
• 3. Tan MHE, Li J, Xu HE, Melcher K, Yong EL. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sinica 2015;36:3–23.
• 4. Lonergan PE, Tindall DJ. Androgen receptor signaling in prostate cancer development and progression. J Carcinog 2011;10:20.
• 5. Sadi MV, Walsh PC, Barrack ER. Immunohistochemical Study of Androgen Receptors in Metastatic Prostate-Cancer - Comparison of Receptor Content and Response to HormonalTherapy. Cancer 1991;67:3057–64.
• 6. Deutsch E, Maggiorella L, Eschwege P, Bourhis J, Soria JC, Abdulkarim B. Environmental, genetic, and molecular features of prostate cancer. Lancet Oncol 2004;5:303–13.
• 7. Heinlein CA, Chang CS. Androgen receptor in prostate cancer. Endocrine Rev 2004;25:276–308.
• 8. Fu MF, Wang CG, Wang J, Zafonte BT, Lisanti MP, Pestell RG.Acetylation in hormone signaling and the cell cycle. Cytokine & Growth Factor Rev 2002;13:259–76.
• 9. Fu MF, Rao M, Wang CG, Sakamaki T, Wang J, Di Vizio D, Zhang XP, Albanese C, Balk S, Chang CS, et al. Acetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth. Mol Cell Biol 2003;23:8563–75.
• 10. Gioeli D, Paschal BM. Post-translational modification of the androgen receptor. Mol Cell Endocrinol 2012;352:70–8.
• 11. Fu M, Liu M, Sauve AA, Jiao X, Zhang X, Wu X, Powell MJ, Yang T, Gu W, Avantaggiati ML, et al. Hormonal control of androgen receptor function through SIRT1. Mol Cell Biol 2006; 26:8122–35.
• 12. Tao RD, Leclerc J, Yildiz K, Park SH, Jung B, Gius D, Ozden O. Changes in gene expression in SIRT3 knockout liver cells. Tr J Biol 2015;39:380–7. 13. Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, Li C, Veenstra TD, Li B, Yu H, et al. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 2011;20:487–99.
• 14. Park SH, Zhu YM, Ozden O, Kim HS, Jiang HY, Deng CX, Gius D, Vassilopoulos A. SIRT2 is a tumor suppressor that connects aging, acetylome, cell cycle signaling, and carcinogenesis. Translational Cancer Res 2012;1:15–21.
• 15. Ozden O. SIRT2-JAK1 Interaction Decreases IL-6 Induced Inflammatory Response in Cancer Cells. Kafkas Univ Vet Fak Derg 2015;21:813–7.
• 16. Dai Y, Ngo D, Forman LW, Qin DC, Jacob J, Faller DV. Sirtuin 1 is required for antagonist-induced transcriptional repression of androgen-responsive genes by the androgen receptor. Mol Endocrinol 2007;21:1807–21.
• 17. Ozden O, Park SH, Wagner BA, Yong Song H, Zhu Y, Vassilopoulos A, Jung B, Buettner GR, Gius D. SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells. Free Radic Biol Med 2014;76:163–72.
• 18. Fraga MF, Agrelo R, Esteller M: Cross-talk between aging and cancer - The epigenetic language. Biogerontol Mech Intervent 2007;1100:60–74.
• 19. Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, Palmberg C, Palotie A, Tammela T, Isola J, Kallioniemi OP. In-Vivo Amplification of the Androgen Receptor Gene and Progression of Human Prostate-Cancer. Nature Genetics 1995;9:401–6.
• 20. Jung-Hynes B, Nihal M, Zhong WX, Ahmad N. Role of Sirtuin Histone Deacetylase Sirt1 In Prostate Cancer A Target For Prostate Cancer Management Via Its Inhibition? Journal of BiolChem 2009;284:3823–32.
• 21. Karadağ MA, Çeçen K, Demir A, Bağcıoğlu M, Kocaaslan R,Sofikerim M. Prostat kanserinde fokal tedavi alternatifleri. KafkasJ Med Sci 2015; 5(1): 18–24.