Advertisement

Using Histone Deacetylase Inhibitors to Analyze the Relevance of HDACs for Translation

  • Darren M. Hutt
  • Daniela Martino Roth
  • Christelle Marchal
  • Marion BouchecareilhEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1510)

Abstract

Gene expression is regulated in part through the reversible acetylation of histones, by the action of histone acetyltransferases (HAT) and histone deacetylases (HDAC). HAT activity results in the addition of acetyl groups on the lysine residues of histone tails leading to decondensation of the chromatin, and increased gene transcription in general, whereas HDACs remove these acetyl groups, thus leading to an overall suppression of gene transcription. Recent evidence has elucidated that histones are not the only components of the proteome that are targeted by HATs and HDACs. A large number of nonhistone proteins undergo posttranslational acetylation. They include proteins involved in mRNA stability, protein localization and degradation, as well as protein–protein and protein–DNA interactions. In recent years, numerous studies have discovered increased HDAC expression and/or activity in numerous disease states, including cancer, where the upregulation of HDAC family members leads to dysregulation of genes and proteins involved in cell proliferation, cell cycle regulation, and apoptosis. These observations have pushed HDAC inhibitors (HDACi) to the forefront of therapeutic development of oncological conditions. HDACi, such as Vorinostat (Suberoylanilide hydroxamic acid (SAHA)), affect cancer cells in part by suppressing the translation of key proteins linked to tumorigenesis, such as cyclin D1 and hypoxia inducible factor 1 alpha (HIF-1α). Herein we describe methodologies to analyze the impact of the HDACi Vorinostat on HIF-1α translational regulation and downstream effectors.

Key words

HDAC HDACi HIF-1α Translation Vorinostat 

Notes

Acknowledgements

This work was funded by grants from CNRS.

References

  1. 1.
    Di Cerbo V, Schneider R (2013) Cancers with wrong HATs: the impact of acetylation. Brief Funct Genomics 12:231–243CrossRefPubMedGoogle Scholar
  2. 2.
    Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M et al (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840CrossRefPubMedGoogle Scholar
  3. 3.
    Mano T, Suzuki T, Tsuji S, Iwata A (2014) Differential effect of HDAC3 on cytoplasmic and nuclear huntingtin aggregates. PLoS One 9, e111277CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ji Q, Hu H, Yang F, Yuan J, Yang Y et al (2014) CRL4B interacts with and coordinates the SIN3A-HDAC complex to repress CDKN1A and drive cell cycle progression. J Cell Sci 127:4679–4691CrossRefPubMedGoogle Scholar
  5. 5.
    Gui CY, Ngo L, Xu WS, Richon VM, Marks PA (2004) Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci U S A 101:1241–1246CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Yan W, Liu S, Xu E, Zhang J, Zhang Y et al (2013) Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8. Oncogene 32:599–609CrossRefPubMedGoogle Scholar
  7. 7.
    Molli PR, Singh RR, Lee SW, Kumar R (2008) MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene. Oncogene 27:1971–1980CrossRefPubMedGoogle Scholar
  8. 8.
    Ropero S, Esteller M (2007) The role of histone deacetylases (HDACs) in human cancer. Mol Oncol 1:19–25CrossRefPubMedGoogle Scholar
  9. 9.
    Barneda-Zahonero B, Parra M (2012) Histone deacetylases and cancer. Mol Oncol 6:579–589CrossRefPubMedGoogle Scholar
  10. 10.
    Choi JH, Kwon HJ, Yoon BI, Kim JH, Han SU et al (2001) Expression profile of histone deacetylase 1 in gastric cancer tissues. Jpn J Cancer Res 92:1300–1304CrossRefPubMedGoogle Scholar
  11. 11.
    Halkidou K, Gaughan L, Cook S, Leung HY, Neal DE et al (2004) Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. Prostate 59:177–189CrossRefPubMedGoogle Scholar
  12. 12.
    Zhang Z, Yamashita H, Toyama T, Sugiura H, Ando Y et al (2005) Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast*. Breast Cancer Res Treat 94:11–16CrossRefPubMedGoogle Scholar
  13. 13.
    Jung KH, Noh JH, Kim JK, Eun JW, Bae HJ et al (2012) HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins. J Cell Biochem 113:2167–2177CrossRefPubMedGoogle Scholar
  14. 14.
    Huang BH, Laban M, Leung CH, Lee L, Lee CK et al (2005) Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ 12:395–404CrossRefPubMedGoogle Scholar
  15. 15.
    Song J, Noh JH, Lee JH, Eun JW, Ahn YM et al (2005) Increased expression of histone deacetylase 2 is found in human gastric cancer. APMIS 113:264–268CrossRefPubMedGoogle Scholar
  16. 16.
    Bhaskara S, Knutson SK, Jiang G, Chandrasekharan MB, Wilson AJ et al (2010) Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18:436–447CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wu LM, Yang Z, Zhou L, Zhang F, Xie HY et al (2010) Identification of histone deacetylase 3 as a biomarker for tumor recurrence following liver transplantation in HBV-associated hepatocellular carcinoma. PLoS One 5:e14460CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Fan J, Lou B, Chen W, Zhang J, Lin S et al (2014) Down-regulation of HDAC5 inhibits growth of human hepatocellular carcinoma by induction of apoptosis and cell cycle arrest. Tumour Biol 35:11523–11532CrossRefPubMedGoogle Scholar
  19. 19.
    Feng GW, Dong LD, Shang WJ, Pang XL, Li JF et al (2014) HDAC5 promotes cell proliferation in human hepatocellular carcinoma by up-regulating Six1 expression. Eur Rev Med Pharmacol Sci 18:811–816PubMedGoogle Scholar
  20. 20.
    Moreno DA, Scrideli CA, Cortez MA, de Paula QR, Valera ET et al (2010) Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia. Br J Haematol 150:665–673CrossRefPubMedGoogle Scholar
  21. 21.
    Milde T, Oehme I, Korshunov A, Kopp-Schneider A, Remke M et al (2010) HDAC5 and HDAC9 in medulloblastoma: novel markers for risk stratification and role in tumor cell growth. Clin Cancer Res 16:3240–3252CrossRefPubMedGoogle Scholar
  22. 22.
    Falkenberg KJ, Johnstone RW (2014) Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov 13:673–691CrossRefPubMedGoogle Scholar
  23. 23.
    West AC, Johnstone RW (2014) New and emerging HDAC inhibitors for cancer treatment. J Clin Invest 124:30–39CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Zhang C, Richon V, Ni X, Talpur R, Duvic M (2005) Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. J Invest Dermatol 125:1045–1052CrossRefPubMedGoogle Scholar
  25. 25.
    Huang L, Pardee AB (2000) Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment. Mol Med 6:849–866PubMedPubMedCentralGoogle Scholar
  26. 26.
    Butler LM, Zhou X, Xu WS, Scher HI, Rifkind RA et al (2002) The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc Natl Acad Sci U S A 99:11700–11705CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Chiao MT, Cheng WY, Yang YC, Shen CC, Ko JL (2013) Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells. Autophagy 9:1509–1526CrossRefPubMedGoogle Scholar
  28. 28.
    Elknerova K, Myslivcova D, Lacinova Z, Marinov I, Uherkova L et al (2011) Epigenetic modulation of gene expression of human leukemia cell lines—induction of cell death and senescence. Neoplasma 58:35–44CrossRefPubMedGoogle Scholar
  29. 29.
    Deroanne CF, Bonjean K, Servotte S, Devy L, Colige A et al (2002) Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 21:427–436CrossRefPubMedGoogle Scholar
  30. 30.
    Liang D, Kong X, Sang N (2006) Effects of histone deacetylase inhibitors on HIF-1. Cell Cycle 5:2430–2435CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kong X, Lin Z, Liang D, Fath D, Sang N et al (2006) Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha. Mol Cell Biol 26:2019–2028CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hutt DM, Roth DM, Vignaud H, Cullin C, Bouchecareilh M (2014) The histone deacetylase inhibitor, Vorinostat, represses hypoxia inducible factor 1 alpha expression through translational inhibition. PLoS One 9, e106224CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kawamata N, Chen J, Koeffler HP (2007) Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells. Blood 110:2667–2673CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Emmrich S, Engeland F, El-Khatib M, Henke K, Obulkasim A et al (2015) miR-139-5p controls translation in myeloid leukemia through EIF4G2. Oncogene 35(14):1822–1831CrossRefPubMedGoogle Scholar
  35. 35.
    Sonnemann J, Marx C, Becker S, Wittig S, Palani CD et al (2014) p53-dependent and p53-independent anticancer effects of different histone deacetylase inhibitors. Br J Cancer 110:656–667CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Darren M. Hutt
    • 1
  • Daniela Martino Roth
    • 1
  • Christelle Marchal
    • 2
  • Marion Bouchecareilh
    • 2
    Email author
  1. 1.Department of Chemical PhysiologyThe Scripps Research InstituteLa JollaUSA
  2. 2.Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095Université de BordeauxBordeauxFrance

Personalised recommendations