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Targeting transcription factor corepressors in tumor cells

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Abstract

By being the “integration” center of transcriptional control as they move and target transcription factors, corepressors fine-tune the epigenetic status of the nucleus. Many of them utilize enzymatic activities to modulate chromatin through histone modification or chromatin remodeling. The clinical and etiological relevance of the corepressors to neoplastic growth is increasingly being recognized. Aberrant expression or function (both loss and gain of) of corepressors has been associated with malignancy and contribute to the generation of transcriptional “inflexibility” manifested as distorted signaling along certain axes. Understanding and predicting the consequences of corepressor alterations in tumor cells has diagnostic and prognostic value, and also have the capacity to be targeted through selective epigenetic regimens. Here, we evaluate corepressors with the most promising therapeutic potential based on their physiological roles and involvement in malignant development, and also highlight areas that can be exploited for molecular targeting of a large proportion of clinical cancers and their complications.

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References

  1. Grivas PD, Kiaris H, Papavassiliou AG (2011) Tackling transcription factors: challenges in antitumor therapy. Trends Mol Med 17:537–538

    Article  PubMed  CAS  Google Scholar 

  2. Lonard DM, O’Malley BW (2007) Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation. Mol Cell 27:691–700

    Article  PubMed  CAS  Google Scholar 

  3. Rosenfeld MG, Lunyak VV, Glass CK (2006) Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev 20:1405–1428

    Article  PubMed  CAS  Google Scholar 

  4. Payankaulam S, Li LM, Arnosti DN (2010) Transcriptional repression: conserved and evolved features. Curr Biol 20:R764–R771

    Article  PubMed  CAS  Google Scholar 

  5. Perissi V, Jepsen K, Glass CK, Rosenfeld MG (2010) Deconstructing repression: evolving models of co-repressor action. Nat Rev Gen 11:109–123

    Article  CAS  Google Scholar 

  6. Stewart MD, Wong J (2009) Nuclear receptor repression: regulatory mechanisms and physiological implications. Prog Mol Biol Transl Sci 87:235–259

    Article  PubMed  CAS  Google Scholar 

  7. Lonard DM, Lanz RB, O’Malley BW (2007) Nuclear receptor coregulators and human disease. Endocr Rev 28:575–587

    Article  PubMed  CAS  Google Scholar 

  8. Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, Zhao K (2009) Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138:1019–1031

    Article  PubMed  CAS  Google Scholar 

  9. Gurevich I, Flores AM, Aneskievich BJ (2007) Corepressors of agonist-bound nuclear receptors. Toxicol Appl Pharmacol 223:288–298

    Article  PubMed  CAS  Google Scholar 

  10. Watson PJ, Fairall L, Schwabe JW (2012) Nuclear hormone receptor co-repressors: structure and function. Mol Cell Endocrinol 348:440–449

    Article  PubMed  CAS  Google Scholar 

  11. Battaglia S, Maguire O, Campbell MJ (2010) Transcription factor co-repressors in cancer biology: roles and targeting. Int J Cancer 126:2511–2519

    PubMed  CAS  Google Scholar 

  12. Biancotto C, Frige G, Minucci S (2010) Histone modification therapy of cancer. Adv Genet 70:341–386

    Article  PubMed  CAS  Google Scholar 

  13. Liu Y, Chen W, Gaudet J, Cheney MD, Roudaia L, Cierpicki T, Klet RC, Hartman K, Laue TM, Speck NA, Bushweller JH (2007) Structural basis for recognition of SMRT/N-CoR by the MYND domain and its contribution to AML1/ETO’s activity. Cancer Cell 11:483–497

    Article  PubMed  CAS  Google Scholar 

  14. Abedin SA, Banwell CM, Colston KW, Carlberg C, Campbell MJ (2006) Epigenetic corruption of VDR signalling in malignancy. Anticancer Res 26:2557–2566

    PubMed  CAS  Google Scholar 

  15. Abedin SA, Thorne JL, Battaglia S, Maguire O, Hornung LB, Doherty AP, Mills IG, Campbell MJ (2009) Elevated NCOR1 disrupts a network of dietary-sensing nuclear receptors in bladder cancer cells. Carcinogenesis 30:449–456

    Article  PubMed  CAS  Google Scholar 

  16. Battaglia S, Maguire O, Thorne JL, Hornung LB, Doig CL, Liu S, Sucheston LE, Bianchi A, Khanim FL, Gommersall LM, Coulter HS, Rakha S, Giddings I, O’Neill LP, Cooper CS, McCabe CJ, Bunce CM, Campbell MJ (2010) Elevated NCOR1 disrupts PPARalpha/gamma signaling in prostate cancer and forms a targetable epigenetic lesion. Carcinogenesis 31:1650–1660

    Article  PubMed  CAS  Google Scholar 

  17. Mann M, Cortez V, Vadlamudi RK (2011) Epigenetics of estrogen receptor signaling: role in hormonal cancer progression and therapy. Cancers 3:1691–1707

    Article  PubMed  CAS  Google Scholar 

  18. Konduri SD, Medisetty R, Liu W, Kaipparettu BA, Srivastava P, Brauch H, Fritz P, Swetzig WM, Gardner AE, Khan SA, Das GM (2010) Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation. Proc Natl Acad Sci USA 107:15081–15086

    Article  PubMed  CAS  Google Scholar 

  19. Hong W, Chen L, Li J, Yao Z (2010) Inhibition of MAP kinase promotes the recruitment of corepressor SMRT by tamoxifen-bound estrogen receptor alpha and potentiates tamoxifen action in MCF-7 cells. Biochem Biophys Res Commun 396:299–303

    Article  PubMed  CAS  Google Scholar 

  20. Reeb CA, Gerlach C, Heinssmann M, Prade I, Ceraline J, Roediger J, Roell D, Baniahmad A (2011) A designed cell-permeable aptamer-based corepressor peptide is highly specific for the androgen receptor and inhibits prostate cancer cell growth in a vector-free mode. Endocrinology 152:2174–2183

    Article  PubMed  CAS  Google Scholar 

  21. Chmelar R, Buchanan G, Need EF, Tilley W, Greenberg NM (2007) Androgen receptor coregulators and their involvement in the development and progression of prostate cancer. Int J Cancer 120:719–733

    Article  PubMed  CAS  Google Scholar 

  22. van de Wijngaart DJ, Dubbink HJ, van Royen ME, Trapman J, Jenster G (2012) Androgen receptor coregulators: recruitment via the coactivator binding groove. Mol Cell Endocrinol 352:57–69

    Article  PubMed  Google Scholar 

  23. Eisold M, Asim M, Eskelinen H, Linke T, Baniahmad A (2009) Inhibition of MAPK-signaling pathway promotes the interaction of the corepressor SMRT with the human androgen receptor and mediates repression of prostate cancer cell growth in the presence of antiandrogens. J Mol Endocrinol 42:429–435

    Article  PubMed  CAS  Google Scholar 

  24. Buchanan G, Need EF, Barrett JM, Bianco-Miotto T, Thompson VC, Butler LM, Marshall VR, Tilley WD, Coetzee GA (2011) Corepressor effect on androgen receptor activity varies with the length of the CAG encoded polyglutamine repeat and is dependent on receptor/corepressor ratio in prostate cancer cells. Mol Cell Endocrinol 342:20–31

    Article  PubMed  CAS  Google Scholar 

  25. Campos B, Bermejo JL, Han L, Felsberg J, Ahmadi R, Grabe N, Reifenberger G, Unterberg A, Herold-Mende C (2011) Expression of nuclear receptor corepressors and class I histone deacetylases in astrocytic gliomas. Cancer Sci 102:387–392

    Article  PubMed  CAS  Google Scholar 

  26. Hsia EY, Goodson ML, Zou JX, Privalsky ML, Chen HW (2010) Nuclear receptor coregulators as a new paradigm for therapeutic targeting. Adv Drug Deliv Rev 62:1227–1237

    Article  PubMed  CAS  Google Scholar 

  27. Lakowski B, Roelens I, Jacob S (2006) CoREST-like complexes regulate chromatin modification and neuronal gene expression. J Mol Neurosci 29:227–239

    Article  PubMed  CAS  Google Scholar 

  28. Lim S, Janzer A, Becker A, Zimmer A, Schule R, Buettner R, Kirfel J (2010) Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis 31:512–520

    Article  PubMed  CAS  Google Scholar 

  29. Schulte JH, Lim S, Schramm A, Friedrichs N, Koster J, Versteeg R, Ora I, Pajtler K, Klein-Hitpass L, Kuhfittig-Kulle S, Metzger E, Schule R, Eggert A, Buettner R, Kirfel J (2009) Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res 69:2065–2071

    Article  PubMed  CAS  Google Scholar 

  30. Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R, Solleder G, Bastian PJ, Ellinger J, Metzger E, Schule R, Buettner R (2006) Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res 66:11341–11347

    Article  PubMed  CAS  Google Scholar 

  31. Huang Y, Stewart TM, Wu Y, Baylin SB, Marton LJ, Perkins B, Jones RJ, Woster PM, Casero RA Jr (2009) Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes. Clin Cancer Res 15:7217–7228

    Article  PubMed  CAS  Google Scholar 

  32. Thillainadesan G, Isovic M, Loney E, Andrews J, Tini M, Torchia J (2008) Genome analysis identifies the p15ink4b tumor suppressor as a direct target of the ZNF217/CoREST complex. Mol Cell Biol 28:6066–6077

    Article  PubMed  CAS  Google Scholar 

  33. Straza MW, Paliwal S, Kovi RC, Rajeshkumar B, Trenh P, Parker D, Whalen GF, Lyle S, Schiffer CA, Grossman SR (2010) Therapeutic targeting of C-terminal binding protein in human cancer. Cell Cycle 9:3740–3750

    Article  PubMed  CAS  Google Scholar 

  34. Chinnadurai G (2009) The transcriptional corepressor CtBP: a foe of multiple tumor suppressors. Cancer Res 69:731–734

    Article  PubMed  CAS  Google Scholar 

  35. Zhao LZ, Chinnadurai G (2010) Incapacitating CtBP to kill cancer. Cell Cycle 9:3645–3646

    PubMed  CAS  Google Scholar 

  36. Deng Y, Liu J, Han G, Lu SL, Wang SY, Malkoski S, Tan AC, Deng C, Wang XJ, Zhang Q (2010) Redox-dependent Brca1 transcriptional regulation by an NADH-sensor CtBP1. Oncogene 29:6603–6608

    Article  PubMed  CAS  Google Scholar 

  37. Grzenda A, Lomberk G, Zhang JS, Urrutia R (2009) Sin3: master scaffold and transcriptional corepressor. Biochim Biophys Acta 1789:443–450

    PubMed  CAS  Google Scholar 

  38. Silverstein RA, Ekwall K (2005) Sin3: a flexible regulator of global gene expression and genome stability. Curr Genet 47:1–17

    Article  PubMed  CAS  Google Scholar 

  39. Ellison-Zelski SJ, Alarid ET (2010) Maximum growth and survival of estrogen receptor-alpha positive breast cancer cells requires the Sin3A transcriptional repressor. Mol Cancer 9:263

    Article  PubMed  Google Scholar 

  40. Farias EF, Petrie K, Leibovitch B, Murtagh J, Chornet MB, Schenk T, Zelent A, Waxman S (2010) Interference with Sin3 function induces epigenetic reprogramming and differentiation in breast cancer cells. Proc Natl Acad Sci USA 107:11811–11816

    Article  PubMed  CAS  Google Scholar 

  41. Hurst DR, Welch DR (2011) Unraveling the enigmatic complexities of BRMS1-mediated metastasis suppression. FEBS Lett 585:3185–3190

    Article  PubMed  CAS  Google Scholar 

  42. Smith KT, Martin-Brown SA, Florens L, Washburn MP, Workman JL (2010) Deacetylase inhibitors dissociate the histone-targeting ING2 subunit from the Sin3 complex. Chem Biol 17:65–74

    Article  PubMed  CAS  Google Scholar 

  43. Reisman D, Glaros S, Thompson EA (2009) The SWI/SNF complex and cancer. Oncogene 28:1653–1668

    Article  PubMed  CAS  Google Scholar 

  44. Hargreaves DC, Crabtree GR (2011) ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res 21:396–420

    Article  PubMed  CAS  Google Scholar 

  45. Wilson BG, Roberts CW (2011) SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 11:481–492

    Article  PubMed  CAS  Google Scholar 

  46. Guan B, Wang TL, Shih IeM (2011) ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers. Cancer Res 71:6718–6727

    Article  PubMed  CAS  Google Scholar 

  47. Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK, Anglesio MS, Kalloger SE, Yang W, Heravi-Moussavi A, Giuliany R, Chow C, Fee J, Zayed A, Prentice L, Melnyk N, Turashvili G, Delaney AD, Madore J, Yip S, McPherson AW, Ha G, Bell L, Fereday S, Tam A, Galletta L, Tonin PN, Provencher D, Miller D, Jones SJ, Moore RA, Morin GB, Oloumi A, Boyd N, Aparicio SA, Shih IeM, Mes-Masson AM, Bowtell DD, Hirst M, Gilks B, Marra MA, Huntsman DG (2010) ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 363:1532–1543

    Article  PubMed  CAS  Google Scholar 

  48. Wang X, Sansam CG, Thom CS, Metzger D, Evans JA, Nguyen PT, Roberts CW (2009) Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex. Cancer Res 69:8094–8101

    Article  PubMed  CAS  Google Scholar 

  49. Lai AY, Wade PA (2011) Cancer biology and NuRD: a multifaceted chromatin remodelling complex. Nat Rev Cancer 11:588–596

    Article  PubMed  CAS  Google Scholar 

  50. Manavathi B, Singh K, Kumar R (2007) MTA family of coregulators in nuclear receptor biology and pathology. Nucl Recept Signal 5:e010

    PubMed  Google Scholar 

  51. Ramirez J, Hagman J (2009) The Mi-2/NuRD complex: a critical epigenetic regulator of hematopoietic development, differentiation and cancer. Epigenetics 4:532–536

    Article  PubMed  CAS  Google Scholar 

  52. Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W, Liang J, Sun L, Yang X, Shi L, Li R, Li Y, Zhang Y, Li Q, Yi X, Shang Y (2009) LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138:660–672

    Article  PubMed  CAS  Google Scholar 

  53. Kai L, Samuel SK, Levenson AS (2010) Resveratrol enhances p53 acetylation and apoptosis in prostate cancer by inhibiting MTA1/NuRD complex. Int J Cancer 126:1538–1548

    PubMed  CAS  Google Scholar 

  54. Asim M, Hafeez BB, Siddiqui IA, Gerlach C, Patz M, Mukhtar H, Baniahmad A (2011) Ligand-dependent corepressor acts as a novel androgen receptor corepressor, inhibits prostate cancer growth, and is functionally inactivated by the Src protein kinase. J Biol Chem 286:37108–37117

    Article  PubMed  CAS  Google Scholar 

  55. Cheng YH, Utsunomiya H, Pavone ME, Yin P, Bulun SE (2011) Retinoic acid inhibits endometrial cancer cell growth via multiple genomic mechanisms. J Mol Endocrinol 46:139–153

    Article  PubMed  CAS  Google Scholar 

  56. Richly H, Aloia L, Di Croce L (2011) Roles of the Polycomb group proteins in stem cells and cancer. Cell Death Dis 2:e204

    Article  PubMed  CAS  Google Scholar 

  57. Jennings BH, Ish-Horowicz D (2008) The Groucho/TLE/Grg family of transcriptional co-repressors. Genome Biol 9:205

    Article  PubMed  Google Scholar 

  58. Papaioannou M, Melle C, Baniahmad A (2007) The coregulator alien. Nucl Recept Signal 5:e008

    PubMed  Google Scholar 

  59. Graham JS, Kaye SB, Brown R (2009) The promises and pitfalls of epigenetic therapies in solid tumours. Eur J Cancer 45:1129–1136

    Article  PubMed  CAS  Google Scholar 

  60. Cerchietti LC, Ghetu AF, Zhu X, Da Silva GF, Zhong S, Matthews M, Bunting KL, Polo JM, Farès C, Arrowsmith CH, Yang SN, Garcia M, Coop A, Mackerell AD Jr, Privé GG, Melnick A (2010) A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell 17:400–411

    Article  PubMed  CAS  Google Scholar 

  61. Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer 11:726–734

    Article  PubMed  CAS  Google Scholar 

  62. Dworkin AM, Huang TH, Toland AE (2009) Epigenetic alterations in the breast: implications for breast cancer detection, prognosis and treatment. Semin Cancer Biol 19:165–171

    Article  PubMed  CAS  Google Scholar 

  63. Bantscheff M, Hopf C, Savitski MM, Dittmann A, Grandi P, Michon AM, Schlegl J, Abraham Y, Becher I, Bergamini G, Boesche M, Delling M, Dumpelfeld B, Eberhard D, Huthmacher C, Mathieson T, Poeckel D, Reader V, Strunk K, Sweetman G, Kruse U, Neubauer G, Ramsden NG, Drewes G (2011) Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat Biotechnol 29:255–265

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Biological Chemistry, University of Athens Medical School, 11527, Athens, Greece

    Aristeidis G. Vaiopoulos, Ioannis D. Kostakis, Kalliopi Ch. Athanasoula & Athanasios G. Papavassiliou

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  1. Aristeidis G. Vaiopoulos
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  2. Ioannis D. Kostakis
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  3. Kalliopi Ch. Athanasoula
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  4. Athanasios G. Papavassiliou
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Correspondence to Athanasios G. Papavassiliou.

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Vaiopoulos, A.G., Kostakis, I.D., Athanasoula, K.C. et al. Targeting transcription factor corepressors in tumor cells. Cell. Mol. Life Sci. 69, 1745–1753 (2012). https://doi.org/10.1007/s00018-012-0986-5

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