Role of Desumoylation in the Development of Prostate Cancer<sup><a href="#FN1" rid="FN1" class=" fn">1</a></sup>

Jinke Cheng

Tasneem Bawa

Peng Lee

Limin Gong

Edward Yeh

^{Department of Cardiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA}

^{Department of Pathology, New York University School of Medicine and New York Harbor VA Medical Center, New York, New York 10016, USA}

Address all correspondence to: Edward T. H. Yeh, Department of Cardiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. E-mail: gro.nosrednadm@heyte

Received 2006 Jun 9; Revised 2006 Jun 9; Accepted 2006 Jun 9.

Abstract

SUMO is a novel ubiquitin-like protein that can covalently modify a large number of nuclear proteins. SUMO modification has emerged as an important regulatory mechanism for protein function and localization. Sumoylation is a dynamic process that is mediated by activating (E1), conjugating (E2), and ligating (E3) enzymes and is readily reversed by a family of SUMO-specific proteases (SENPs). Since SUMO was discovered 10 years ago, the biologic contribution of this posttranslational modification has remained unclear. In this review, we report that SENP1, a member of the SENP family, is overexpressed in human prostate cancer specimens. The induction of SENP1 is observed with the chronic exposure of prostate cancer cells to androgen and/or interleukin (IL) 6. SENP1 upregulation modulates the transcriptional activity of androgen receptors (ARs) and c-Jun, as well as cyclin D1 expression. Initial in vivo data from transgenic mice indicate that overexpression of SENP1 in the prostate leads to the development of prostatic intraepithelial neoplasia at an early age. Collectively, these studies indicate that overexpression of SENP1 is associated with prostate cancer development.

Keywords: SUMO, Sentrin, SENP, SUMO-specific protease, prostate cancer

Abstract

Footnotes

^{This work was supported by the National Institutes of Health (RO1 CA 80089) and the Department of Defense (CDMRP PC040121).}

Footnotes

References

1. Okura T, Gong L, Kamitani T, Wada T, Okura I, Wei CF, Chang HM, Yeh ETProtection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin. J Immunol. 1996;157:4277–4281.[PubMed][Google Scholar]
2. Mahajan R, Delphin C, Guan T, Gerace L, Melchior FA small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell. 1997;88:97–107.[PubMed][Google Scholar]
3. Matunis MJ, Coutavas E, Blobel GA novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. J Cell Biol. 1996;135:1457–1470.[Google Scholar]
4. Boddy MN, Howe K, Etkin LD, Solomon E, Freemont PSPIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia. Oncogene. 1996;13:971–982.[PubMed][Google Scholar]
5. Shen Z, Pardington-Purtymun PE, Comeaux JC, Moyzis RK, Chen DJUBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins. Genomics. 1996;36:271–279.[PubMed][Google Scholar]
6. Kamitani T, Kito K, Nguyen HP, Fukuda-Kamitani T, Yeh ETCharacterization of a second member of the sentrin family of ubiquitin-like proteins. J Biol Chem. 1998;273:11349–11353.[PubMed][Google Scholar]
7. Johnson ES, Schwienhorst I, Dohmen RJ, Blobel GThe ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer. EMBO J. 1997;16:5509–5519.[Google Scholar]
8. Gong L, Li B, Millas S, Yeh ETMolecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex. FEBS Lett. 1999;448:185–189.[PubMed][Google Scholar]
9. Dohmen RJ, Stappen R, McGrath JP, Forrova H, Kolarov J, Goffeau A, Varshavsky AAn essential yeast gene encoding a homolog of ubiquitin-activating enzyme. J Biol Chem. 1995;270:18099–18109.[PubMed][Google Scholar]
10. Gong L, Kamitani T, Fujise K, Caskey LS, Yeh ETPreferential interaction of sentrin with a ubiquitin-conjugating enzyme, Ubc9. J Biol Chem. 1997;272:28198–28201.[PubMed][Google Scholar]
11. Johnson ES, Blobel GUbc9p is the conjugating enzyme for the ubiquitin-like protein Smt3p. J Biol Chem. 1997;272:26799–26802.[PubMed][Google Scholar]
12. Johnson ES, Gupta AAAn E3-like factor that promotes SUMO conjugation to the yeast septins. Cell. 2001;106:735–744.[PubMed][Google Scholar]
13. Kahyo T, Nishida T, Yasuda HInvolvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol Cell. 2001;8:713–718.[PubMed][Google Scholar]
14. Pichler A, Gast A, Seeler JS, Dejean A, Melchior FThe nucleoporin RanBP2 hasSUMO1 E3 ligase activity. Cell. 2002;108:109–120.[PubMed][Google Scholar]
15. Kagey MH, Melhuish TA, Wotton DThe polycomb protein pc2 is a SUMO E3. Cell. 2003;113:127–137.[PubMed][Google Scholar]
16. Kamitani T, Nguyen HP, Kito K, Fukuda-Kamitani T, Yeh ETCovalent modification of PML by the sentrin family of ubiquitin-like proteins. J Biol Chem. 1998;273:3117–3120.[PubMed][Google Scholar]
17. Gostissa M, Hengstermann A, Fogal V, Sandy P, Schwarz SE, Scheffner M, Del Sal GActivation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J. 1999;18:6462–6471.[Google Scholar]
18. Buschmann T, Fuchs SY, Lee CG, Pan ZQ, Ronai ZSUMO-1 modification of Mdm2 prevents its self-ubiquitination and increases Mdm2 ability to ubiquitinate p53. Cell. 2000;101:753–762.[PubMed][Google Scholar]
19. Mao Y, Desai SD, Liu LFSUMO-1 conjugation to human DNA topoisomerase II isozymes. J Biol Chem. 2000;275:26066–26073.[PubMed][Google Scholar]
20. Mao Y, Sun M, Desai SD, Liu LFSUMO-1 conjugation to topoisomerase I: a possible repair response to topoisomerase-mediated DNA damage. Proc Natl Acad Sci USA. 2000;97:4046–4051.[Google Scholar]
21. Poukka H, Karvonen U, Janne OA, Palvimo JJCovalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1) Proc Natl Acad Sci USA. 2000;97:14145–14150.[Google Scholar]
22. Chauchereau A, Amazit L, Quesne M, Guiochon-Mantel A, Milgrom ESumoylation of the progesterone receptor and of the coactivator SRC-1. J Biol Chem. 2003;14:14.[PubMed][Google Scholar]
23. Kotaja N, Karvonen U, Janne OA, Palvimo JJPIAS proteins modulate transcription factors by functioning as SUMO-1 ligases. Mol Cell Biol. 2002;22:5222–5234.[Google Scholar]
24. Girdwood D, Bumpass D, Vaughan OA, Thain A, Anderson LA, Snowden AW, Garcia-Wilson E, Perkins ND, Hay RTp300 transcriptional repression is mediated by SUMO modification. Mol Cell. 2003;11:1043–1054.[PubMed][Google Scholar]
25. David G, Neptune MA, DePinho RASUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities. J Biol Chem. 2002;277:23658–23663.[PubMed][Google Scholar]
26. Desterro JM, Rodriguez MS, Hay RTSUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Mol Cell. 1998;2:233–239.[PubMed][Google Scholar]
27. Hay RT, Vuillard L, Desterro JM, Rodriguez MSControl of NF-kappa B transcriptional activation by signal induced proteolysis of I kappa B alpha. Philos Trans R Soc Lond B Biol Sci. 1999;354:1601–1609.[Google Scholar]
28. Kirsh O, Seeler JS, Pichler A, Gast A, Muller S, Miska E, Mathieu M, Harel-Bellan A, Kouzarides T, Melchior F, et al The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J. 2002;21:2682–2691.[Google Scholar]
29. Lehembre F, Muller S, Pandolfi PP, Dejean ARegulation of Pax3 transcriptional activity by SUMO-1-modified PML. Oncogene. 2001;20:1–9.[PubMed][Google Scholar]
30. Kishi A, Nakamura T, Nishio Y, Maegawa H, Kashiwagi ASumoylation of Pdx1 is associated with its nuclear localization and insulin gene activation. Am J Physiol Endocrinol Metab. 2003;284:E830–E840.[PubMed][Google Scholar]
31. Ross S, Best JL, Zon LI, Gill GSUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization. Mol Cell. 2002;10:831–842.[PubMed][Google Scholar]
32. Tojo M, Matsuzaki K, Minami T, Honda Y, Yasuda H, Chiba T, Saya H, Fujii-Kuriyama Y, Nakao MThe aryl hydrocarbon receptor nuclear transporter is modulated by the SUMO-1 conjugation system. J Biol Chem. 2002;277:46576–46585.[PubMed][Google Scholar]
33. Muller S, Berger M, Lehembre F, Seeler JS, Haupt Y, Dejean Ac-Jun and p53 activity is modulated by SUMO-1 modification. J Biol Chem. 2000;275:13321–13329.[PubMed][Google Scholar]
34. Yeh ET, Gong L, Kamitani TUbiquitin-like proteins: new wines in new bottles. Gene. 2000;248:1–14.[PubMed][Google Scholar]
35. Best JL, Ganiatsas S, Agarwal S, Changou A, Salomoni P, Shirihai O, Meluh PB, Pandolfi PP, Zon LISUMO-1 protease-1 regulates gene transcription through PML. Mol Cell. 2002;10:843–855.[PubMed][Google Scholar]
36. Hang J, Dasso MAssociation of the human SUMO-1 protease SENP2 with the nuclear pore. J Biol Chem. 2002;277:19961–19966.[PubMed][Google Scholar]
37. Kim KI, Baek SH, Jeon YJ, Nishimori S, Suzuki T, Uchida S, Shimbara N, Saitoh H, Tanaka K, Chung CHA new SUMO-1-specific protease, SUSP1, that is highly expressed in reproductive organs. J Biol Chem. 2000;275:14102–14106.[PubMed][Google Scholar]
38. Nishida T, Kaneko F, Kitagawa M, Yasuda HCharacterization of a novel mammalian SUMO-1/Smt3-specific isopeptidase, a homologue of rat axam, which is an axin-binding protein promoting beta-catenin degradation. J Biol Chem. 2001;276:39060–39066.[PubMed][Google Scholar]
39. Nishida T, Tanaka H, Yasuda HA novel mammalian Smt3-specific isopeptidase 1 (SMT3IP1) localized in the nucleolus at interphase. Eur J Biochem. 2000;267:6423–6427.[PubMed][Google Scholar]
40. Gong L, Millas S, Maul GG, Yeh ETDifferential regulation of sentrinized proteins by a novel sentrin-specific protease. J Biol Chem. 2000;275:3355–3359.[PubMed][Google Scholar]
41. Zhang H, Saitoh H, Matunis MJEnzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex. Mol Cell Biol. 2002;22:6498–6508.[Google Scholar]
42. Itahana Y, Yeh ETH, Zhang YNucleocytoplasmic shuttling modulates activity and ubiquitination-dependent turnover of SUMO-specific protease 2. Mol Cell Biol. 2006;26:4675–4689.[Google Scholar]
43. Gong L, Yeh ETCharacterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3. J Biol Chem. 2006;281:15869–15877.[PubMed][Google Scholar]
44. McKenna NJ, O'Malley BWCombinatorial control of gene expression by nuclear receptors and coregulators. Cell. 2002;108:465–474.[PubMed][Google Scholar]
45. Bossis G, Malnou CE, Farras R, Andermarcher E, Hipskind R, Rodriguez M, Schmidt D, Muller S, Jariel-Encontre I, Piechaczyk MDown-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol. 2005;25:6964–6979.[Google Scholar]
46. Kotaja N, Karvonen U, Janne OA, Palvimo JJThe nuclear receptor interaction domain of GRIP1 is modulated by covalent attachment of SUMO-1. J Biol Chem. 2002;277:30283–30288.[PubMed][Google Scholar]
47. Colombo R, Boggio R, Seiser C, Draetta GF, Chiocca SThe adenovirus protein Gam1 interferes with sumoylation of histone deacetylase 1. EMBO Rep. 2002;3:1062–1068.[Google Scholar]
48. Tussie-Luna MI, Bayarsaihan D, Seto E, Ruddle FH, Roy ALPhysical and functional interactions of histone deacetylase 3 with TFII-I family proteins and PIASxbeta. Proc Natl Acad Sci USA. 2002;99:12807–12812.[Google Scholar]
49. Dunn C, Wiltshire C, MacLaren A, Gillespie DAMolecular mechanism and biological functions of c-Jun N-terminal kinase signalling via the c-Jun transcription factor. Cell Signal. 2002;14:585–593.[PubMed][Google Scholar]
50. Lee JS, See RH, Deng T, Shi YAdenovirus E1A downregulates cJun- and JunB-mediated transcription by targeting their coactivator p300. Mol Cell Biol. 1996;16:4312–4326.[Google Scholar]
51. Vries RG, Prudenziati M, Zwartjes C, Verlaan M, Kalkhoven E, Zantema AA specific lysine in c-Jun is required for transcriptional repression by E1A and is acetylated by p300. EMBO J. 2001;20:6095–6103.[Google Scholar]
52. Albanese C, D'Amico M, Reutens AT, Fu M, Watanabe G, Lee RJ, Kitsis RN, Henglein B, Avantaggiati M, Somasundaram K, et al Activation ofthecyclin D1 gene by the E1A-associated protein p300 through AP-1 inhibits cellular apoptosis. J Biol Chem. 1999;274:34186–34195.[PubMed][Google Scholar]
53. Gregory DJ, Garcia-Wilson E, Poole JC, Snowden AW, Roninson IB, Perkins NDInduction of transcription through the p300 CRD1 motif by p21WAF1/CIP1 is core promoter specific and cyclin dependent kinase independent. Cell Cycle. 2002;1:343–350.[PubMed][Google Scholar]
54. Ait-Si-Ali S, Ramirez S, Barre FX, Dkhissi F, Magnaghi-Jaulin L, Girault JA, Robin P, Knibiehler M, Pritchard LL, Ducommun B, et al Histone acetyltransferase activity of CBP is controlled by cycle-dependent kinases and oncoprotein E1A. Nature. 1998;396:184–186.[PubMed][Google Scholar]
55. Snowden AW, Anderson LA, Webster GA, Perkins NDA novel transcriptional repression domain mediates p21(WAF1/CIP1) induction of p300 transactivation. Mol Cell Biol. 2000;20:2676–2686.[Google Scholar]
56. Perkins ND, Felzien LK, Betts JC, Leung K, Beach DH, Nabel GJRegulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator. Science. 1997;275:523–527.[PubMed][Google Scholar]
57. Cheng J, Wang D, Wang Z, Yeh ETSENP1 enhances androgen receptor-dependent transcription through desumoylation of histone deacetylase I. Mol Cell Biol. 2004;24:6021–6028.[Google Scholar]
58. Cheng J, Perkins ND, Yeh ETDifferential regulation of c-Jun-dependent transcription by SUMO-specific proteases. J Biol Chem. 2005;280:14492–14498.[PubMed][Google Scholar]
59. Nelson WG, De Marzo AM, Isaacs WBProstate cancer. N Engl J Med. 2003;349:366–381.[PubMed][Google Scholar]
60. DeMarzo AM, Nelson WG, Isaacs WB, Epstein JIPathological and molecular aspects of prostate cancer. Lancet. 2003;361:955–964.[PubMed][Google Scholar]
61. Culig Z, Klocker H, Bartsch G, Steiner H, Hobisch AAndrogen receptors in prostate cancer. J Urol. 2003;170:1363–1369.[PubMed][Google Scholar]
62. Tiniakos DG, Mitropoulos D, Kyroudi-Voulgari A, Soura K, Kittas CExpression of c-jun oncogene in hyperplastic and carcinomatous human prostate. Urology. 2006;67:204–208.[PubMed][Google Scholar]
63. Meng MV, Shinohara K, Grossfeld GDSignificance of highgrade prostatic intraepithelial neoplasia on prostate biopsy. Urol Oncol. 2003;21:145–151.[PubMed][Google Scholar]
64. Murray AWRecycling the cell cycle: cyclins revisited. Cell. 2004;116:221–234.[PubMed][Google Scholar]
65. Harper JW, Adams PDCyclin-dependent kinases. Chem Rev. 2001;101:2511–2526.[PubMed][Google Scholar]
66. Fu M, Wang C, Li Z, Sakamaki T, Pestell RGCyclin D1: normal and abnormal functions [minireview] Endocrinology. 2004;145:5439–5447.[PubMed][Google Scholar]
67. Wang C, Li Z, Fu M, Bouras T, Pestell RGSignal transduction mediated by cyclin D1: from mitogens to cell proliferation: a molecular target with therapeutic potential. Cancer Treat Res. 2004;119:217–237.[PubMed][Google Scholar]
68. Stacey DWCyclin D1 serves as a cell cycle regulatory switch in actively proliferating cells. Curr Opin Cell Biol. 2003;15:158–163.[PubMed][Google Scholar]
69. Culig Z, Hobisch A, Herold M, Hittmair A, Thurnher M, Eder IE, Cronauer MV, Rieser C, Ramoner R, Bartsch G, et al Interleukin 1beta mediates the modulatory effects of monocytes on LNCaP human prostate cancer cells. Br J Cancer. 1998;78:1004–1011.[Google Scholar]
70. Mizokami A, Gotoh A, Yamada H, Keller ET, Matsumoto TTumor necrosis factor-alpha represses androgen sensitivity in the LNCaP prostate cancer cell line. J Urol. 2000;164:800–805.[PubMed][Google Scholar]
71. Nakashima J, Tachibana M, Ueno M, Miyajima A, Baba S, Murai MAssociation between tumor necrosis factor in serum and cachexia in patients with prostate cancer. Clin Cancer Res. 1998;4:1743–1748.[PubMed][Google Scholar]
72. Lee HJ, Chang CRecent advances in androgen receptor action. Cell Mol Life Sci. 2003;60:1613–1622.[PubMed][Google Scholar]
73. Yang L, Wang L, Lin HK, Kan PY, Xie S, Tsai MY, Wang PH, Chen YT, Chang CInterleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells. Biochem Biophys Res Commun. 2003;305:462–469.[PubMed][Google Scholar]
74. Ueda T, Bruchovsky N, Sadar MDActivation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J Biol Chem. 2002;277:7076–7085.[PubMed][Google Scholar]
75. Mohler JL, Gregory CW, Ford OH, III, Kim D, Weaver CM, Petrusz P, Wilson EM, French FSThe androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10:440–448.[PubMed][Google Scholar]
76. Chlenski A, Nakashiro K, Ketels KV, Korovaitseva GI, Oyasu RAndrogen receptor expression in androgen-independent prostate cancer cell lines. Prostate. 2001;47:66–75.[PubMed][Google Scholar]