Posttranslational regulation of androgen dependent and independent androgen receptor activities in prostate cancer
Simeng Wenab,Yuanjie Niua**(),Haojie Huangbcd*()
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
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.
. [J]. Asian Journal of Urology, 2020, 7(3): 203-218.
Simeng Wen,Yuanjie Niu,Haojie Huang. Posttranslational regulation of androgen dependent and independent androgen receptor activities in prostate cancer. Asian Journal of Urology, 2020, 7(3): 203-218.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA A Cancer J Clin 2018; 68:7-30.
[2]
Miyamoto H, Messing EM, Chang C. Androgen deprivation therapy for prostate cancer: current status and future prospects. Prostate 2004; 61:332-53.
[3]
Wen S, Chang HC, Tian J, Shang Z, Niu Y, Chang C. Stromal androgen receptor roles in the development of normal prostate, benign prostate hyperplasia, and prostate cancer. Am J Pathol 2015; 185:293-301.
[4]
Dehm SM, Tindall DJ. Molecular regulation of androgen action in prostate cancer. J Cell Biochem 2006; 99:333-44.
Gelmann EP. Molecular biology of the androgen receptor. J Clin Oncol 2002; 20:3001-15.
[7]
Ding D, Xu L, Menon M, Reddy GP, Barrack ER. Effect of GGC (glycine) repeat length polymorphism in the human androgen receptor on androgen action. Prostate 2005; 62:133-9.
[8]
Jenster G, van der Korput HA, Trapman J, Brinkmann AO. Identification of two transcription activation units in the Nterminal domain of the human androgen receptor. J Biol Chem 1995; 270:7341-6.
[9]
Wong CI, Zhou ZX, Sar M, Wilson EM. Steroid requirement for androgen receptor dimerization and DNA binding. Modulation by intramolecular interactions between the NH2-terminal and steroid-binding domains. J Biol Chem 1993; 268:19004-12.
[10]
Kasper S, Rennie PS, Bruchovsky N, Sheppard PC, Cheng H, Lin L, et al. Cooperative binding of androgen receptors to two DNA sequences is required for androgen induction of the probasin gene. J Biol Chem 1994; 269:31763-9.
[11]
Shaffer PL, Jivan A, Dollins DE, Claessens F, Gewirth DT. Structural basis of androgen receptor binding to selective androgen response elements. Proc Natl Acad Sci U S A 2004; 101:4758-63.
[12]
He B, Gampe Jr RT, Kole AJ, Hnat AT, Stanley TB, An G, et al. Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance. Mol Cell 2004; 16:425-38.
[13]
Estebanez-Perpina E, Moore JM, Mar E, Delgado-Rodrigues E, Nguyen P, Baxter JD, et al. The molecular mechanisms of coactivator utilization in ligand-dependent transactivation by the androgen receptor. J Biol Chem 2005; 280:8060-8.
[14]
Zoubeidi A, Zardan A, Beraldi E, Fazli L, Sowery R, Rennie P, et al. Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity. Cancer Res 2007; 67:10455-65.
[15]
Kuil CW, Berrevoets CA, Mulder E. Ligand-induced conformational alterations of the androgen receptor analyzed by limited trypsinization. Studies on the mechanism of antiandrogen action. J Biol Chem 1995; 270:27569-76.
Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview. Endocr Rev 2002; 23:175-200.
[18]
van der Steen T, Tindall DJ, Huang H. Posttranslational modification of the androgen receptor in prostate cancer. Int J Mol Sci 2013; 14:14833-59.
[19]
Zhou ZX, Kemppainen JA, Wilson EM. Identification of three proline-directed phosphorylation sites in the human androgen receptor. Mol Endocrinol 1995; 9:605-15.
[20]
Chen S, Xu Y, Yuan X, Bubley GJ, Balk SP. Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1. Proc Natl Acad Sci U S A 2006; 103:15969-74.
[21]
Yang CS, Xin HW, Kelley JB, Spencer A, Brautigan DL, Paschal BM. Ligand binding to the androgen receptor induces conformational changes that regulate phosphatase interactions. Mol Cell Biol 2007; 27:3390-404.
[22]
Russo JW, Liu X, Ye H, Calagua C, Chen S, Voznesensky O, et al. Phosphorylation of androgen receptor serine 81 is associated with its reactivation in castration-resistant prostate cancer. Cancer Lett 2018; 438:97-104.
[23]
Adelaiye-Ogala R, Damayanti NP, Orillion AR, Arisa S, Chintala S, Titus MA, et al. Therapeutic targeting of sunitinib-induced AR phosphorylation in renal cell carcinoma. Cancer Res 2018; 78:2886-96.
[24]
Jorda R, Buckova Z, Reznickova E, Bouchal J, Krystof V. Selective inhibition reveals cyclin-dependent kinase 2 as another kinase that phosphorylates the androgen receptor at serine 81. Biochim Biophys Acta Mol Cell Res 2018; 1865:354-63.
[25]
Ngan ES, Hashimoto Y, Ma ZQ, Tsai MJ, Tsai SY. Overexpression of Cdc25B, an androgen receptor coactivator, in prostate cancer. Oncogene 2003; 22:734-9.
[26]
Maddison LA, Huss WJ, Barrios RM, Greenberg NM. Differential expression of cell cycle regulatory molecules and evidence for a “cyclin switch” during progression of prostate cancer. Prostate 2004; 58:335-44.
[27]
Ozen M, Ittmann M. Increased expression and activity of CDC25C phosphatase and an alternatively spliced variant in prostate cancer. Clin Cancer Res 2005; 11:4701-6.
[28]
Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J, et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 2009; 138:245-56.
[29]
Liu X, Gao Y, Ye H, Gerrin S, Ma F, Wu Y, et al. Positive feedback loop mediated by protein phosphatase 1a mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer. Nucleic Acids Res 2017; 45:3738-51.
[30]
Gordon V, Bhadel S, Wunderlich W, Zhang J, Ficarro SB, Mollah SA, et al. CDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation. Mol Endocrinol 2010; 24:2267-80.
[31]
Tarricone C, Dhavan R, Peng J, Areces LB, Tsai LH, Musacchio A. Structure and regulation of the CDK5- p25(nck5a) complex. Mol Cell 2001; 8:657-69.
[32]
Williamson M, de Winter P, Masters JR. Plexin-B1 signalling promotes androgen receptor translocation to the nucleus. Oncogene 2016; 35:1066-72.
[33]
Grey J, Jones D, Wilson L, Nakjang S, Clayton J, Temperley R, et al. Differential regulation of the androgen receptor by protein phosphatase regulatory subunits. Oncotarget 2017; 9:3922-35.
[34]
Karantanos T, Karanika S, Wang J, Yang G, Dobashi M, Park S, et al. Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer. Oncotarget 2016; 7:46321-34.
[35]
Li L, Ren CH, Tahir SA, Ren C, Thompson TC. Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. Mol Cell Biol 2003; 23:9389-404.
[36]
Hsu FN, Chen MC, Chiang MC, Lin E, Lee YT, Huang PH, et al. Regulation of androgen receptor and prostate cancer growth by cyclin-dependent kinase 5. J Biol Chem 2011; 286:33141-9.
[37]
Luo J, Tian J, Chou F, Lin C, Xing EZ, Zuo L, et al. Targeting the androgen receptor (AR) with AR degradation enhancer ASC-J9(R) led to increase docetaxel sensitivity via suppressing the p21 expression. Cancer Lett 2019; 444:35-44.
[38]
Zhong J, Ding L, Bohrer LR, Pan Y, Liu P, Zhang J, et al. p300 acetyltransferase regulates androgen receptor degradation and PTEN-deficient prostate tumorigenesis. Cancer Res 2014; 74:1870-80.
[39]
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; 19:575-86.
[40]
Deep G, Oberlies NH, Kroll DJ, Agarwal R. Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway. Oncogene 2008; 27:3986-98.
[41]
Gorowska-Wojtowicz E, Hejmej A, Kaminska A, Pardyak L, Kotula-Balak M, Dulinska-Litewka J, et al. Anti-androgen 2- hydroxyflutamide modulates cadherin, catenin and androgen receptor phosphorylation in androgen-sensitive LNCaP and androgen-independent PC3 prostate cancer cell lines acting via PI3K/Akt and MAPK/ERK1/2 pathways. Toxicol In Vitro 2017; 40:324-35.
[42]
Lin HK, Yeh S, Kang HY, Chang C. Akt suppresses androgeninduced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci U S A 2001; 98:7200-5.
[43]
Linn DE, Yang X, Xie Y, Alfano A, Deshmukh D, Wang X, et al. Differential regulation of androgen receptor by PIM-1 kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases. J Biol Chem 2012; 287:22959-68.
[44]
Ha S, Iqbal NJ, Mita P, Ruoff R, Gerald WL, Lepor H, et al. Phosphorylation of the androgen receptor by PIM1 in hormone refractory prostate cancer. Oncogene 2013; 32:3992-4000.
[45]
Varisli L, Gonen-Korkmaz C, Syed HM, Bogurcu N, Debelec- Butuner B, Erbaykent-Tepedelen B, et al. Androgen regulated HN1 leads proteosomal degradation of androgen receptor (AR) and negatively influences AR mediated transactivation in prostate cells. Mol Cell Endocrinol 2012; 350:107-17.
[46]
Zong H, Chi Y, Wang Y, Yang Y, Zhang L, Chen H, et al. Cyclin D3/CDK11p58 complex is involved in the repression of androgen receptor. Mol Cell Biol 2007; 27:7125-42.
[47]
Kim Y, Kim J, Jang SW, Ko J. The role of sLZIP in cyclin D3- mediated negative regulation of androgen receptor transactivation and its involvement in prostate cancer. Oncogene 2015; 34:226-36.
[48]
Yang CS, Vitto MJ, Busby SA, Garcia BA, Kesler CT, Gioeli D, et al. Simian virus 40 small t antigen mediates conformationdependent transfer of protein phosphatase 2A onto the androgen receptor. Mol Cell Biol 2005; 25:1298-308.
[49]
McCall P, Adams CE, Willder JM, Bennett L, Qayyum T, Orange C, et al. Androgen receptor phosphorylation at serine 308 and serine 791 predicts enhanced survival in castrate resistant prostate cancer patients. Int J Mol Sci 2013; 14:16656-71.
[50]
Lindqvist J, Imanishi SY, Torvaldson E, Malinen M, Remes M, ?rn F, et al. Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells. Mol Biol Cell 2015; 26:1971-84.
[51]
Koryakina Y, Knudsen KE, Gioeli D. Cell-cycle-dependent regulation of androgen receptor function. Endocr Relat Cancer 2015; 22:249-64.
[52]
Chymkowitch P, Le May N, Charneau P, Compe E, Egly JM. The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process. EMBO J 2011; 30:468-79.
[53]
Han Y, Huang W, Liu J, Liu D, Cui Y, Huang R, et al. Triptolide inhibits the AR signaling pathway to suppress the proliferation of enzalutamide resistant prostate cancer cells. Theranostics 2017; 7:1914-27.
[54]
Ponguta LA, Gregory CW, French FS, Wilson EM. Site-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castrationrecurrent prostate cancer. J Biol Chem 2008; 283:20989-1001.
[55]
Patek S, Willder J, Heng J, Taylor B, Horgan P, Leung H, et al. Androgen receptor phosphorylation status at serine 578 predicts poor outcome in prostate cancer patients. Oncotarget 2017; 8:4875-87.
[56]
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; 288:3359-69.
[57]
Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD, et al. Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem 2002; 277:29304-14.
[58]
Gioeli D, Black BE, Gordon V, Spencer A, Kesler CT, Eblen ST, et al. Stress kinase signaling regulates androgen receptor phosphorylation, transcription, and localization. Mol Endocrinol 2006; 20:503-15.
[59]
Wong HY, Burghoorn JA, Van Leeuwen M, De Ruiter PE, Schippers E, Blok LJ, et al. Phosphorylation of androgen receptor isoforms. Biochem J 2004; 383:267-76.
[60]
Zhou ZX, Sar M, Simental JA, Lane MV, Wilson EM. A liganddependent bipartite nuclear targeting signal in the human androgen receptor. Requirement for the DNA-binding domain and modulation by NH2-terminal and carboxyl-terminal sequences. J Biol Chem 1994; 269:13115-23.
[61]
Jenster G, van der Korput JA, Trapman J, Brinkmann AO. Functional domains of the human androgen receptor. J Steroid Biochem Mol Biol 1992; 41:671-5.
[62]
Picard D, Yamamoto KR. Two signals mediate hormonedependent nuclear localization of the glucocorticoid receptor. EMBO J 1987; 6:3333-40.
[63]
Poukka H, Aarnisalo P, Santti H, Janne OA, Palvimo JJ. Coregulator small nuclear RING finger protein (SNURF) enhances Sp1- and steroid receptor-mediated transcription by different mechanisms. J Biol Chem 2000; 275:571-9.
[64]
Chen S, Kesler CT, Paschal BM, Balk SP. Androgen receptor phosphorylation and activity are regulated by an association with protein phosphatase 1. J Biol Chem 2009; 284:25576-84.
[65]
Liu X, Han W, Gulla S, Simon NI, Gao Y, Cai C, et al. Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation. Oncotarget 2016; 7:1754-64.
[66]
Zboray L, Pluciennik A, Curtis D, Liu Y, Berman-Booty LD, Orr C, et al. Preventing the androgen receptor N/C interaction delays disease onset in a mouse model of SBMA. Cell Rep 2015; 13:2312-23.
[67]
Langley E, Zhou ZX, Wilson EM. Evidence for an anti-parallel orientation of the ligand-activated human androgen receptor dimer. J Biol Chem 1995; 270:29983-90.
[68]
La Montagna R, Caligiuri I, Maranta P, Lucchetti C, Esposito L, Paggi MG, et al. Androgen receptor serine 81 mediates Pin1 interaction and activity. Cell Cycle 2012; 11:3415-20.
[69]
Willder JM, Heng SJ, McCall P, Adams CE, Tannahill C, Fyffe G, et al. Androgen receptor phosphorylation at serine 515 by Cdk1 predicts biochemical relapse in prostate cancer patients. Br J Canc 2013; 108:139-48.
[70]
Palazzolo I, Burnett BG, Young JE, Brenne PL, La Spada AR, Fischbeck KH, et al. Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity. Hum Mol Genet 2007; 16:1593-603.
[71]
Rocha J, Zouanat FZ, Zoubeidi A, Hamel L, Benidir T, Scarlata E, et al. The Fer tyrosine kinase acts as a downstream interleukin-6 effector of androgen receptor activation in prostate cancer. Mol Cell Endocrinol 2013; 381:140-9.
[72]
Mahajan NP, Liu Y, Majumder S, Warren MR, Parker CE, Mohler JL, et al. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proc Natl Acad Sci U S A 2007; 104:8438-43.
[73]
Mahajan K, Challa S, Coppola D, Lawrence H, Luo Y, Gevariya H, et al. Effect of Ack1 tyrosine kinase inhibitor on ligand-independent androgen receptor activity. Prostate 2010; 70:1274-85.
[74]
Karaca M, Liu Y, Zhang Z, De Silva D, Parker JS, Earp HS, et al. Mutation of androgen receptor N-terminal phosphorylation site Tyr-267 leads to inhibition of nuclear translocation and DNA binding. PLoS One 2015;10:e0126270. 10.1371/journal.pone.0126270.eCollection2015.
doi: 10.1371/journal.pone.0126270
pmid: 25950519
[75]
Guo Z, Dai B, Jiang T, Xu K, Xie Y, Kim O, et al. Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell 2006; 10:309-19.
[76]
Chattopadhyay I, Wang J, Qin M, Gao L, Holtz R, Vessella RL, et al. Src promotes castration-recurrent prostate cancer through androgen receptor-dependent canonical and noncanonical transcriptional signatures. Oncotarget 2017; 8:10324-47.
[77]
Drake JM, Graham NA, Stoyanova T, Sedghi A, Goldstein AS, Cai H, et al. Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression. Proc Natl Acad Sci U S A 2012; 109:1643-8.
[78]
Fu M, Liu M, Sauve AA, Jiao X, Zhang X, Wu X, et al. Hormonal control of androgen receptor function through SIRT1. Mol Cell Biol 2006; 26:8122-35.
[79]
Fu M, Wang C, Reutens AT, Wang J, Angeletti RH, Siconolfi- Baez L, et al. p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation. J Biol Chem 2000; 275:20853-60.
[80]
Yang L, Lin C, Jin C, Yang JC, Tanasa B, Li W, et al. lncRNAdependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 2013; 500:598-602.
[81]
Prensner JR, Sahu A, Iyer MK, Malik R, Chandler B, Asangani IA, et al. The IncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancer. Oncotarget 2014; 5:1434-8.
[82]
Wang Z, Wang Z, Guo J, Li Y, Bavarva JH, Qian C, et al. Inactivation of androgen-induced regulator ARD1 inhibits androgen receptor acetylation and prostate tumorigenesis. Proc Natl Acad Sci U S A 2012; 109:3053-8.
[83]
DePaolo JS, Wang Z, Guo J, Zhang G, Qian C, Zhang H, et al. Acetylation of androgen receptor by ARD1 promotes dissociation from HSP90 complex and prostate tumorigenesis. Oncotarget 2016; 7:71417-28.
[84]
Fu M, Rao M, Wang C, Sakamaki T, Wang J, Di Vizio D, et al. Acetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth. Mol Cell Biol 2003; 23:8563-75.
[85]
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.
[86]
Montie HL, Pestell RG, Merry DE. SIRT1 modulates aggregation and toxicity through deacetylation of the androgen receptor in cell models of SBMA. J Neurosci 2011; 31:17425-36.
[87]
Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 2014; 510:278-82.
[88]
Welti J, Sharp A, Yuan W, Dolling D, Nava Rodrigues D, Figueiredo I, et al. Targeting bromodomain and extraterminal (BET) family proteins in castration-resistant prostate cancer (CRPC). Clin Cancer Res 2018; 24:3149-62.
[89]
Ko S, Ahn J, Song CS, Kim S, Knapczyk-Stwora K, Chatterjee B. Lysine methylation and functional modulation of androgen receptor by Set9 methyltransferase. Mol Endocrinol 2011; 25:433-44.
[90]
Chen Y, Chi P, Rockowitz S, Iaquinta PJ, Shamu T, Shukla S, et al. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nat Med 2013; 19:1023-9.
[91]
Mounir Z, Korn JM, Westerling T, Lin F, Kirby CA, Schirle M, et al. ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor. Elife 2016; 5:e13964. https://doi.org/10.7554/eLife.13964.
doi: 10.7554/eLife.13964
pmid: 27183006
[92]
Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 2012; 338:1465-9.
[93]
Liu Q, Wang G, Li Q, Jiang W, Kim JS, Wang R, et al. Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer. Int J Cancer 2019; 145:415-26.
[94]
Fong KW, Zhao JC, Kim J, Li S, Yang YA, Song B, et al. Polycomb- mediated disruption of an androgen receptor feedback loop drives castration-resistant prostate cancer. Cancer Res 2017; 77:412-22.
[95]
Zhang Y, Zheng D, Zhou T, Song H, Hulsurkar M, Su N, et al. Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers. Nat Commun 2018; 9:4080.
pmid: 30287808
[96]
Dardenne E, Beltran H, Benelli M, Gayvert K, Berger A, Puca L, et al. N-myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell 2016; 30:563-77.
[97]
Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 2017; 355:78-83.
[98]
Jing Y, Nguyen MM, Wang D, Pascal LE, Guo W, Xu Y, et al. DHX15 promotes prostate cancer progression by stimulating Siah2-mediated ubiquitination of androgen receptor. Oncogene 2018; 37:638-50.
[99]
Zhu S, Zhao D, Yan L, Jiang W, Kim JS, Gu B, et al. BMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1. Nat Commun 2018; 9:500. https://doi.org/10.1038/s41467-018-02863-3.
pmid: 29402932
[100]
Liu C, Lou W, Yang JC, Liu L, Armstrong CM, Lombard AP, et al. Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer. Nat Commun 2018; 9:4700. https://doi.org/10.1038/s41467-018-07178-x.
pmid: 30446660
[101]
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; 15:270-82.
[102]
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; 21:4037-48.
[103]
He B, Bai S, Hnat AT, Kalman RI, Minges JT, Patterson C, et al. An androgen receptor NH2-terminal conserved motif interacts with the COOH terminus of the Hsp70-interacting protein (CHIP). J Biol Chem 2004; 279:30643-53.
[104]
Felten A, Brinckmann D, Landsberg G, Scheidtmann KH. Zipper-interacting protein kinase is involved in regulation of ubiquitination of the androgen receptor, thereby contributing to dynamic transcription complex assembly. Oncogene 2013; 32:4981-8.
[105]
Moon SJ, Jeong BC, Kim HJ, Lim JE, Kwon GY, Kim JH. DBC1 promotes castration-resistant prostate cancer by positively regulating DNA binding and stability of AR-V7. Oncogene 2018; 37:1326-39.
[106]
Liu N, Guo Z, Xia X, Liao Y, Zhang F, Huang C, et al. Auranofin lethality to prostate cancer includes inhibition of proteasomal deubiquitinases and disrupted androgen receptor signaling. Eur J Pharmacol 2019; 846:1-11.
[107]
McClurg UL, Cork DMW, Darby S, Ryan-Munden CA, Nakjang S, Mendes Cortes L, et al. Identification of a novel K311 ubiquitination site critical for androgen receptor transcriptional activity. Nucleic Acids Res 2017; 45:1793-804.
[108]
Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 2015; 163:1011-25.
[109]
An J, Wang C, Deng Y, Yu L, Huang H. Destruction of fulllength androgen receptor by wild-type SPOP, but not prostate-cancer-associated mutants. Cell Rep 2014; 6:657-69.
[110]
Kim MS, Je EM, Oh JE, Yoo NJ, Lee SH. Mutational and expressional analyses of SPOP, a candidate tumor suppressor gene, in prostate, gastric and colorectal cancers. APMIS 2013; 121:626-33.
[111]
Geng C, Rajapakshe K, Shah SS, Shou J, Eedunuri VK, Foley C, et al. Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer. Cancer Res 2014; 74:5631-43.
[112]
Li C, Ao J, Fu J, Lee DF, Xu J, Lonard D, et al. Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1. Oncogene 2011; 30:4350-64.
[113]
Geng C, He B, Xu L, Barbieri CE, Eedunuri VK, Chew SA, et al. Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover. Proc Natl Acad Sci U S A 2013; 110:6997-7002.
[114]
Zhang P, Wang D, Zhao Y, Ren S, Gao K, Ye Z, et al. Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation. Nat Med 2017; 23:1055-62.
[115]
Jin X, Yan Y, Wang D, Ding D, Ma T, Ye Z, et al. DUB3 promotes BET inhibitor resistance and cancer progression by deubiquitinating BRD4. Mol Cell 2018; 71:592-605.e4. https://doi.org/10.1016/j.molcel.2018.06.036.
[116]
Yan Y, An J, Yang Y, Wu D, Bai Y, Cao W, et al. Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTENor SPOP-mutated prostate cancer. EMBO Mol Med 2018; 10:e8478. https://doi.org/10.15252/emmm.201708478.
pmid: 29523594
[117]
Boysen G, Rodrigues DN, Rescigno P, Seed G, Dolling D, Riisnaes R, et al. SPOP-mutated/CHD1-deleted lethal prostate cancer and abiraterone sensitivity. Clin Cancer Res 2018; 24:5585-93.
[118]
Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015; 161:1215-28.
[119]
Hines J, Gough JD, Corson TW, Crews CM. Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs. Proc Natl Acad Sci U S A 2013; 110:8942-7.
[120]
Bondeson DP, Mares A, Smith IE, Ko E, Campos S, Miah AH, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol 2015; 11:611-7.
[121]
Sakamoto KM, Kim KB, Verma R, Ransick A, Stein B, Crews CM, et al. Development of Protacs to target cancerpromoting proteins for ubiquitination and degradation. Mol Cell Proteom 2003; 2:1350-8.
[122]
Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci U S A 2001; 98:8554-9.
[123]
Rodriguez-Gonzalez A, Cyrus K, Salcius M, Kim K, Crews CM, Deshaies RJ, et al. Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. Oncogene 2008; 27:7201-11.
[124]
Schneekloth Jr JS, Fonseca FN, Koldobskiy M, Mandal A, Deshaies R, Sakamoto K, et al. Chemical genetic control of protein levels: selective in vivo targeted degradation. J Am Chem Soc 2004; 126:3748-54.
[125]
Geiss-Friedlander R, Melchior F. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 2007; 8:947-56.
[126]
Wang Y, Dasso M. SUMOylation and deSUMOylation at a glance. J Cell Sci 2009; 122:4249-52.
[127]
Nishida T, Yasuda H. PIAS1 and PIASxalpha function as SUMOE3 ligases toward androgen receptor and repress androgen receptor-dependent transcription. J Biol Chem 2002; 277:41311-7.
[128]
Kotaja N, Karvonen U, Janne OA, Palvimo JJ. PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases. Mol Cell Biol 2002; 22:5222-34.
[129]
Poukka H, Karvonen U, Janne OA, Palvimo JJ. Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1). Proc Natl Acad Sci U S A 2000; 97:14145-50.
[130]
Rytinki M, Kaikkonen S, Sutinen P, Paakinaho V, Rahkama V, Palvimo JJ. Dynamic SUMOylation is linked to the activity cycles of androgen receptor in the cell nucleus. Mol Cell Biol 2012; 32:4195-205.
[131]
Kaikkonen S, Jaaskelainen T, Karvonen U, Rytinki MM, Makkonen H, Gioeli D, et al. SUMO-specific protease 1 (SENP1) reverses the hormone-augmented SUMOylation of androgen receptor and modulates gene responses in prostate cancer cells. Mol Endocrinol 2009; 23:292-307.
[132]
Callewaert L, Verrijdt G, Haelens A, Claessens F. Differential effect of small ubiquitin-like modifier (SUMO)-ylation of the androgen receptor in the control of cooperativity on selective versus canonical response elements. Mol Endocrinol 2004; 18:1438-49.
[133]
Wu R, Cui Y, Yuan X, Yuan H, Wang Y, He J, et al. SUMO-specific protease 1 modulates cadmiumaugmented transcriptional activity of androgen receptor (AR) by reversing AR SUMOylation. Toxicol Lett 2014; 229:405-13.
[134]
Sutinen P, Malinen M, Heikkinen S, Palvimo JJ. SUMOylation modulates the transcriptional activity of androgen receptor in a target gene and pathway selective manner. Nucleic Acids Res 2014; 42:8310-9.
[135]
Jin L, Garcia J, Chan E, de la Cruz C, Segal E, Merchant M, et al. Therapeutic targeting of the CBP/p300 bromodomain blocks the growth of castration-resistant prostate cancer. Cancer Res 2017; 77:5564-75.
