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C-terminal binding protein-2 regulates response of epithelial ovarian cancer cells to histone deacetylase inhibitors

Oncogene volume 32, pages 3896–3903 (2013)Cite this article

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Abstract

Ovarian cancer survival rates have stagnated in the last 20 years despite the development of novel chemotherapeutic agents. Modulators of gene expression, such as histone deacetylase (HDAC) inhibitors, are among the new agents being used in clinical trials. Predictors of sensitivity to chemotherapy have remained elusive. In this study, we show that the expression of the transcriptional corepressor C-terminal binding protein-2 (CtBP2) is elevated in human ovarian tumors. Downregulation of CtBP2 expression in ovarian cancer cell lines using short-hairpin RNA strategy suppressed the growth rate and migration of the resultant cancer cells. The knockdown cell lines also showed upregulation of HDAC activity and increased sensitivity to selected HDAC inhibitors. Conversely, forced expression of wild-type CtBP2 in the knockdown cell lines reversed HDAC activity and partially rescued cellular sensitivity to the HDAC inhibitors. We propose that CtBP2 is an ovarian cancer oncogene that regulates gene expression program by modulating HDAC activity. CtBP2 expression may be a surrogate indicator of cellular sensitivity to HDAC inhibitors.

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References

  1. Altekruse S, Kosary C, Krapcho M, Neyman N, Aminou R, Waldron W et al. SEER Cancer Statistics Review, 1975-2007. National Cancer Institue, Bethesda, MD, USA, 2010.

    Google Scholar 

  2. Tang L, Yang J, Ng SK, Rodriguez N, Choi PW, Vitonis A et al. Autoantibody profiling to identify biomarkers of key pathogenic pathways in mucinous ovarian cancer. Eur J Cancer 2010; 46: 170–179.

    Article  CAS  Google Scholar 

  3. Katsanis N, Fisher EM . A novel C-terminal binding protein (CTBP2) is closely related to CTBP1, an adenovirus E1A-binding protein, and maps to human chromosome 21q21.3. Genomics 1998; 47: 294–299.

    Article  CAS  Google Scholar 

  4. Boyd JM, Subramanian T, Schaeper U, La Regina M, Bayley S, Chinnadurai G . A region in the C-terminus of adenovirus 2/5 E1a protein is required for association with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation, tumorigenesis and metastasis. EMBO J 1993; 12: 469–478.

    Article  CAS  Google Scholar 

  5. Turner J, Crossley M . Cloning and characterization of mCtBP2, a co-repressor that associates with basic Kruppel-like factor and other mammalian transcriptional regulators. EMBO J 1998; 17: 5129–5140.

    Article  CAS  Google Scholar 

  6. Chinnadurai G . Transcriptional regulation by C-terminal binding proteins. Int J Biochem Cell Biol 2007; 39: 1593–1607.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Grooteclaes M, Deveraux Q, Hildebrand J, Zhang Q, Goodman RH, Frisch SM . C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs. Proc Natl Acad Sci USA 2003; 100: 4568–4573.

    Article  CAS  Google Scholar 

  9. Grooteclaes ML, Frisch SM . Evidence for a function of CtBP in epithelial gene regulation and anoikis. Oncogene 2000; 19: 3823–3828.

    Article  CAS  Google Scholar 

  10. Chinnadurai G . CtBP, an unconventional transcriptional corepressor in development and oncogenesis. Mol Cell 2002; 9: 213–224.

    Article  CAS  Google Scholar 

  11. Sierra J, Yoshida T, Joazeiro CA, Jones KA . The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes. Genes Dev 2006; 20: 586–600.

    Article  CAS  Google Scholar 

  12. Shi Y, Sawada J, Sui G, Affar el B, Whetstine JR, Lan F et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 2003; 422: 735–738.

    Article  CAS  Google Scholar 

  13. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB . Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003; 370: 737–749.

    Article  CAS  Google Scholar 

  14. Minucci S, Pelicci PG . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6: 38–51.

    Article  CAS  Google Scholar 

  15. Yoo CB, Jones PA . Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 2006; 5: 37–50.

    Article  CAS  Google Scholar 

  16. Glaser KB . HDAC inhibitors: clinical update and mechanism-based potential. Biochem Pharmacol 2007; 74: 659–671.

    Article  CAS  Google Scholar 

  17. Lin X, Sun B, Liang M, Liang YY, Gast A, Hildebrand J et al. Opposed regulation of corepressor CtBP by SUMOylation and PDZ binding. Mol Cell 2003; 11: 1389–1396.

    Article  CAS  Google Scholar 

  18. Zhao LJ, Subramanian T, Zhou Y, Chinnadurai G . Acetylation by p300 regulates nuclear localization and function of the transcriptional corepressor CtBP2. J Biol Chem 2006; 281: 4183–4189.

    Article  CAS  Google Scholar 

  19. Fang M, Li J, Blauwkamp T, Bhambhani C, Campbell N, Cadigan KM . C-terminal-binding protein directly activates and represses Wnt transcriptional targets in Drosophila. EMBO J 2006; 25: 2735–2745.

    Article  CAS  Google Scholar 

  20. Hildebrand JD, Soriano P . Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development. Mol Cell Biol 2002; 22: 5296–5307.

    Article  CAS  Google Scholar 

  21. Hamada F, Bienz M . The APC tumor suppressor binds to C-terminal binding protein to divert nuclear beta-catenin from TCF. Dev Cell 2004; 7: 677–685.

    Article  CAS  Google Scholar 

  22. Engers R, Gabbert HE . Mechanisms of tumor metastasis: cell biological aspects and clinical implications. J Cancer Res Clin Oncol 2000; 126: 682–692.

    Article  CAS  Google Scholar 

  23. Moon RT, Kohn AD, De Ferrari GV, Kaykas A . WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 2004; 5: 691–701.

    Article  CAS  Google Scholar 

  24. Cuilliere-Dartigues P, El-Bchiri J, Krimi A, Buhard O, Fontanges P, Flejou JF et al. TCF-4 isoforms absent in TCF-4 mutated MSI-H colorectal cancer cells colocalize with nuclear CtBP and repress TCF-4-mediated transcription. Oncogene 2006; 25: 4441–4448.

    Article  CAS  Google Scholar 

  25. Zhang CL, McKinsey TA, Lu JR, Olson EN . Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor. J Biol Chem 2001; 276: 35–39.

    Article  CAS  Google Scholar 

  26. Khan N, Jeffers M, Kumar S, Hackett C, Boldog F, Khramtsov N et al. Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem J 2008; 409: 581–589.

    Article  CAS  Google Scholar 

  27. Fournel M, Bonfils C, Hou Y, Yan PT, Trachy-Bourget MC, Kalita A et al. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther 2008; 7: 759–768.

    Article  CAS  Google Scholar 

  28. Huang KC, Park DC, Ng SK, Lee JY, Ni X, Ng WC et al. Selenium binding protein 1 in ovarian cancer. Int J Cancer 2006; 118: 2433–2440.

    Article  CAS  Google Scholar 

  29. Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T et al. Chemical phylogenetics of histone deacetylases. Nat Chem Biol 2010; 6: 238–243.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank critical reading of the manuscript by Professor YF Wong. We acknowledge the provision of belinostat, vorinostat, MGCD0103 from Selleck Inc. LB was supported by Ruth N White Gynecologic Oncology Research Fellowship. The Laboratory of Gynecologic Oncology was partly supported by Robert and Deborah First Fund, the Sperling Family Fund Foundation, Women’s Cancer Program and Gillette Center for Women’s Cancer from Dana-Farber Cancer Institute, Ovarian Cancer Research Foundation, Adler Foundation, Inc., and Friends of Dana-Farber Cancer Institute.

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Authors and Affiliations

  1. Department of Obstetrics/Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Boston, MA, USA

    L Barroilhet, J Yang, K Hasselblatt, J A Rauh-Hain, R S Berkowitz & S-W Ng

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    R M Paranal & J E Bradner

  3. School of Medicine, Griffith Health Institute, Griffith University, Meadowbrook, Queensland, Australia

    S-K Ng

  4. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    W R Welch

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  1. L Barroilhet
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  2. J Yang
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  10. S-W Ng
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Correspondence to S-W Ng.

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Barroilhet, L., Yang, J., Hasselblatt, K. et al. C-terminal binding protein-2 regulates response of epithelial ovarian cancer cells to histone deacetylase inhibitors. Oncogene 32, 3896–3903 (2013). https://doi.org/10.1038/onc.2012.380

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