Regulation of Androgen Receptor by E3 Ubiquitin Ligases: for More or Less

Bo Li, Wenfu Lu, Zhenbang Chen

Abstract


Prostate cancer (PCa) primarily depends on androgen receptor (AR) signaling pathway for the initiation and growth as well as recurrence after castration [1]. Androgen deprivation therapy (ADT) effectively alleviates the symptoms of the malignancy to arrest further growth of the primary tumors or the progression of metastasis in patients with the advanced PCa. However, the relapse occurs in many patients after a short period, and PCa cells eventually become insensitive to ADT - termed castration resistant prostate cancer [2, 3].  Tremendous advancements have been achieved to decipher the mechanisms on AR signaling, and 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 is an E3 ubiquitin ligase for AR protein, and SKP2 levels determine AR expression through ubiquitin-mediated proteasomal degradation.  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.

 

 


Full Text:

PDF

References


Cooperberg MR, Small EJ, D'Amico A, Carroll PR. The evolving role of androgen deprivation therapy in the management of prostate cancer. Minerva Urol Nefrol 2003;55: 219-238.

Huggins C. Effect of Orchiectomy and Irradiation on Cancer of the Prostate. Ann Surg 1942;115: 1192-1200.

Nakai Y, Nishimura K, Nakayama M, Uemura M, Takayama H, Nonomura N, et al. Weekly, low-dose docetaxel combined with estramustine for Japanese castration-resistant prostate cancer: its efficacy and safety profile compared with tri-weekly standard-dose treatment. Int J Clin Oncol 2014;19: 165-172.

Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64: 9-29.

Chang CS, Kokontis J, Liao ST. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 1988;240: 324-326.

Trapman J, Klaassen P, Kuiper GG, van der Korput JA, Faber PW, van Rooij HC, et al. Cloning, structure and expression of a cDNA encoding the human androgen receptor. Biochem Biophys Res Commun 1988;153: 241-248.

Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are present in human genital skin fibroblasts. Proc Natl Acad Sci U S A 1994;91: 1234-1238.

van Royen ME, van Cappellen WA, de Vos C, Houtsmuller AB, Trapman J. Stepwise androgen receptor dimerization. J Cell Sci 2012;125: 1970-1979.

Wang L, Hsu CL, Ni J, Wang PH, Yeh S, Keng P, et al. Human checkpoint protein hRad9 functions as a negative coregulator to repress androgen receptor transactivation in prostate cancer cells. Mol Cell Biol 2004;24: 2202-2213.

Lu W, Xie Y, Ma Y, Matusik RJ, Chen Z. ARF represses androgen receptor transactivation in prostate cancer. Mol Endocrinol 2013;27: 635-648.

Aragon-Ching JB, Dahut WL. Novel Androgen Deprivation Therapy (ADT) in the Treatment of Advanced Prostate Cancer. Drug Discov Today Ther Strateg 2010;7: 31-35.

Huggins C. Prostatic cancer treated by orchiectomy; the five year results. J Am Med Assoc 1946;131: 576-581.

Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol 2002;167: 948-951; discussion 952.

Payton S. Prostate cancer: Contemporary aDt usage reflects established benefit. Nat Rev Urol 2010;7: 644.

Petrylak DP. Current state of castration-resistant prostate cancer. Am J Manag Care 2013;19: s358-365.

Pezaro C, Attard G. Prostate cancer in 2011: redefining the therapeutic landscape for CRPC. Nat Rev Urol 2012;9: 63-64.

Ciechanover A, Elias S, Heller H, Hershko A. "Covalent affinity" purification of ubiquitin-activating enzyme. J Biol Chem 1982;257: 2537-2542.

Hershko A, Ciechanover A. The ubiquitin pathway for the degradation of intracellular proteins. Prog Nucleic Acid Res Mol Biol 1986;33: 19-56, 301.

Hershko A, Ciechanover A. The ubiquitin system for protein degradation. Annu Rev Biochem 1992;61: 761-807.

Wilkinson KD. Protein ubiquitination: a regulatory post-translational modification. Anticancer Drug Des 1987;2: 211-229.

Hadden JW. Thymopoietin, ubiquitin and the differentiation of lymphocytes. Clin Bull 1975;5: 66-67.

Schlesinger DH, Goldstein G. Molecular conservation of 74 amino acid sequence of ubiquitin between cattle and man. Nature 1975;255: 423-424.

Schlesinger DH, Goldstein G, Niall HD. The complete amino acid sequence of ubiquitin, an adenylate cyclase stimulating polypeptide probably universal in living cells. Biochemistry 1975;14: 2214-2218.

Xu K, Shimelis H, Linn DE, Jiang R, Yang X, Sun F, et al. Regulation of androgen receptor transcriptional activity and specificity by RNF6-induced ubiquitination. Cancer Cell 2009;15: 270-282.

Lin HK, Wang L, Hu YC, Altuwaijri S, Chang C. Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. EMBO J 2002;21: 4037-4048.

Liu T, Li Y, Gu H, Zhu G, Li J, Cao L, et al. p21-Activated kinase 6 (PAK6) inhibits prostate cancer growth via phosphorylation of androgen receptor and tumorigenic E3 ligase murine double minute-2 (Mdm2). J Biol Chem 2013;288: 3359-3369.

Murata S, Minami Y, Minami M, Chiba T, Tanaka K. CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep 2001;2: 1133-1138.

Qi J, Tripathi M, Mishra R, Sahgal N, Fazli L, Ettinger S, et al. The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity. Cancer Cell 2013;23: 332-346.

Kanda T. A ubiquitin-protein ligase (E3) mutation of Saccharomyces cerevisiae suppressed by co-overexpression of two ubiquitin-specific processing proteases. Genes Genet Syst 1996;71: 75-83.

Shalizi A, Bilimoria PM, Stegmuller J, Gaudilliere B, Yang Y, Shuai K, et al. PIASx is a MEF2 SUMO E3 ligase that promotes postsynaptic dendritic morphogenesis. J Neurosci 2007;27: 10037-10046.

Li B, Lu W, Yang Q, Yu X, Matusik RJ, Chen Z. Skp2 regulates androgen receptor through ubiquitin-mediated degradation independent of Akt/mTOR pathways in prostate cancer. Prostate 2014;74: 421-432.

Yu ZK, Gervais JL, Zhang H. Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21(CIP1/WAF1) and cyclin D proteins. Proc Natl Acad Sci U S A 1998;95: 11324-11329.

Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1999;1: 193-199.

Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H. p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Curr Biol 1999;9: 661-664.

Yam CH, Ng RW, Siu WY, Lau AW, Poon RY. Regulation of cyclin A-Cdk2 by SCF component Skp1 and F-box protein Skp2. Mol Cell Biol 1999;19: 635-645.

Zhan F, Colla S, Wu X, Chen B, Stewart JP, Kuehl WM, et al. CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms. Blood 2007;109: 4995-5001.

Bhatt S, Xiao Z, Meng Z, Katzenellenbogen BS. Phosphorylation by p38 mitogen-activated protein kinase promotes estrogen receptor alpha turnover and functional activity via the SCF(Skp2) proteasomal complex. Mol Cell Biol 2012;32: 1928-1943.

Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z, et al. The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell 2012;149: 1098-1111.

Gao D, Inuzuka H, Tseng A, Wei W. Akt finds its new path to regulate cell cycle through modulating Skp2 activity and its destruction by APC/Cdh1. Cell Div 2009;4: 11.

Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 2011;19: 575-586.

Ha S, Ruoff R, Kahoud N, Franke TF, Logan SK. Androgen receptor levels are upregulated by Akt in prostate cancer. Endocr Relat Cancer 2011;18: 245-255.

Miyake H, Pollak M, Gleave ME. Castration-induced up-regulation of insulin-like growth factor binding protein-5 potentiates insulin-like growth factor-I activity and accelerates progression to androgen independence in prostate cancer models. Cancer Res 2000;60: 3058-3064.

Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 2008;68: 4447-4454.




DOI: http://dx.doi.org/10.14800/rci.122

Refbacks

  • There are currently no refbacks.




Copyright (c) 2014 Bo Li, Wenfu Lu, Zhenbang Chen

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.