Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation

Nature volume 487, pages 114–118 (2012)Cite this article

Subjects

Abstract

Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism and ageing1,2. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets and physiological functions have been unclear. Here we show that SIRT7 is an NAD+-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase that stabilizes the transformed state of cancer cells. Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. The spectrum of SIRT7 target genes is defined in part by its interaction with the cancer-associated E26 transformed specific (ETS) transcription factor ELK4, and comprises numerous genes with links to tumour suppression. Notably, selective hypoacetylation of H3K18Ac has been linked to oncogenic transformation, and in patients is associated with aggressive tumour phenotypes and poor prognosis3,4,5,6. We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells, including anchorage-independent growth and escape from contact inhibition. Moreover, SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by the viral oncoprotein E1A. Finally, SIRT7 depletion markedly reduces the tumorigenicity of human cancer cell xenografts in mice. Together, our work establishes SIRT7 as a highly selective H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs and tumour formation in vivo.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: SIRT7 is a chromatin-associated H3K18Ac-specific deacetylase.
Figure 2: SIRT7 binds to gene promoters and couples H3K18 deacetylation to transcriptional repression.
Figure 3: SIRT7 is stabilized at target promoters by interaction with the ETS family transcription factor ELK4.
Figure 4: SIRT7 depletion reverses cancer cell phenotypes and inhibits tumour growth in vivo.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The SIRT7 ChIP-sequencing data are deposited in NIH Gene Expression Omnibus under accession number GSE28149. In addition, raw and processed data are available on our project website, http://dldcc-web.brc.bcm.edu/lilab/SIRT7/.

References

  1. Haigis, M. C. & Sinclair, D. A. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5, 253–295 (2010)

    Article  CAS  Google Scholar 

  2. Longo, V. D. & Kennedy, B. K. Sirtuins in aging and age-related disease. Cell 126, 257–268 (2006)

    Article  CAS  Google Scholar 

  3. Ferrari, R. et al. Epigenetic reprogramming by adenovirus e1a. Science 321, 1086–1088 (2008)

    Article  ADS  CAS  Google Scholar 

  4. Horwitz, G. A. et al. Adenovirus small e1a alters global patterns of histone modification. Science 321, 1084–1085 (2008)

    Article  ADS  CAS  Google Scholar 

  5. Manuyakorn, A. et al. Cellular histone modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma: results from RTOG 9704. J. Clin. Oncol. 28, 1358–1365 (2010)

    Article  CAS  Google Scholar 

  6. Seligson, D. B. et al. Global levels of histone modifications predict prognosis in different cancers. Am. J. Pathol. 174, 1619–1628 (2009)

    Article  CAS  Google Scholar 

  7. Vakhrusheva, O. et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ. Res. 102, 703–710 (2008)

    Article  CAS  Google Scholar 

  8. Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C. & Horikawa, I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol. Biol. Cell 16, 4623–4635 (2005)

    Article  CAS  Google Scholar 

  9. Hassig, C. A. et al. A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proc. Natl Acad. Sci. USA 95, 3519–3524 (1998)

    Article  ADS  CAS  Google Scholar 

  10. Wang, Z. et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nature Genet. 40, 897–903 (2008)

    Article  CAS  Google Scholar 

  11. Steeg, P. S. et al. Evidence for a novel gene associated with low tumor metastatic potential. J. Natl. Cancer Inst. 80, 200–204 (1988)

    Article  CAS  Google Scholar 

  12. Leal, J. F. et al. Cellular senescence bypass screen identifies new putative tumor suppressor genes. Oncogene 27, 1961–1970 (2008)

    Article  CAS  Google Scholar 

  13. Bryne, J. C. et al. JASPAR, the open access database of transcription factor-binding profiles: new content and tools in the 2008 update. Nucleic Acids Res. 36, D102–D106 (2008)

    Article  CAS  Google Scholar 

  14. Galang, C. K., Muller, W. J., Foos, G., Oshima, R. G. & Hauser, C. A. Changes in the expression of many Ets family transcription factors and of potential target genes in normal mammary tissue and tumors. J. Biol. Chem. 279, 11281–11292 (2004)

    Article  CAS  Google Scholar 

  15. Kaikkonen, S., Makkonen, H., Rytinki, M. & Palvimo, J. J. SUMOylation can regulate the activity of ETS-like transcription factor 4. Biochim. Biophys. Acta 1799, 555–560 (2010)

    Article  CAS  Google Scholar 

  16. O’Geen, H. et al. Genome-wide binding of the orphan nuclear receptor TR4 suggests its general role in fundamental biological processes. BMC Genomics 11, 689 (2010)

    Article  Google Scholar 

  17. Ashraf, N. et al. Altered sirtuin expression is associated with node-positive breast cancer. Br. J. Cancer 95, 1056–1061 (2006)

    Article  CAS  Google Scholar 

  18. de Nigris, F. et al. Isolation of a SIR-like gene, SIR-T8, that is overexpressed in thyroid carcinoma cell lines and tissues. Br. J. Cancer 86, 917–923 (2002)

    Article  CAS  Google Scholar 

  19. Frye, R. ‘SIRT8’ expressed in thyroid cancer is actually SIRT7. Br. J. Cancer 87, 1479 (2002)

    Article  CAS  Google Scholar 

  20. Makkonen, H. et al. Identification of ETS-like transcription factor 4 as a novel androgen receptor target in prostate cancer cells. Oncogene 27, 4865–4876 (2008)

    Article  CAS  Google Scholar 

  21. Braithwaite, A. W. et al. Adenovirus-induced alterations of the cell growth cycle: a requirement for expression of E1A but not of E1B. J. Virol. 45, 192–199 (1983)

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Amsterdam, A. et al. Many ribosomal protein genes are cancer genes in zebrafish. PLoS Biol. 2, E139 (2004)

    Article  Google Scholar 

  23. Ebert, B. L. et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 451, 335–339 (2008)

    Article  ADS  CAS  Google Scholar 

  24. Ford, E. et al. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev. 20, 1075–1080 (2006)

    Article  MathSciNet  CAS  Google Scholar 

  25. Hansen, M. et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans . Aging Cell 6, 95–110 (2007)

    Article  CAS  Google Scholar 

  26. Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009)

    Article  ADS  CAS  Google Scholar 

  27. Lombard, D. B., Schwer, B., Alt, F. W. & Mostoslavsky, R. SIRT6 in DNA repair, metabolism and ageing. J. Intern. Med. 263, 128–141 (2008)

    Article  CAS  Google Scholar 

  28. Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008)

    Article  ADS  CAS  Google Scholar 

  29. Dahl, J. A. & Collas, P. Q2ChIP, a quick and quantitative chromatin immunoprecipitation assay, unravels epigenetic dynamics of developmentally regulated genes in human carcinoma cells. Stem Cells 25, 1037–1046 (2007)

    Article  CAS  Google Scholar 

  30. Chua, K. F. et al. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab. 2, 67–76 (2005)

    Article  CAS  Google Scholar 

  31. Mendez, J. & Stillman, B. Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis. Mol. Cell. Biol. 20, 8602–8612 (2000)

    Article  CAS  Google Scholar 

  32. Hung, T. et al. ING4 mediates crosstalk between histone H3 K4 trimethylation and H3 acetylation to attenuate cellular transformation. Mol. Cell 33, 248–256 (2009)

    Article  CAS  Google Scholar 

  33. Shi, X. et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442, 96–99 (2006)

    Article  ADS  CAS  Google Scholar 

  34. Garcia, B. A. et al. Chemical derivatization of histones for facilitated analysis by mass spectrometry. Nature Protocols 2, 933–938 (2007)

    Article  CAS  Google Scholar 

  35. Plazas-Mayorca, M. D. et al. One-pot shotgun quantitative mass spectrometry characterization of histones. J. Proteome Res. 8, 5367–5374 (2009)

    Article  CAS  Google Scholar 

  36. Rappsilber, J., Ishihama, Y. & Mann, M. Stop and go extraction tips for matrix-assisted laser desorption/ionization, nanoelectrospray, and LC/MS sample pretreatment in proteomics. Anal. Chem. 75, 663–670 (2003)

    Article  CAS  Google Scholar 

  37. Moqtaderi, Z. et al. Genomic binding profiles of functionally distinct RNA polymerase III transcription complexes in human cells. Nature Struct. Mol. Biol. 17, 635–640 (2010)

    Article  CAS  Google Scholar 

  38. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008)

    Article  Google Scholar 

  39. Dennis, G., Jr et al. DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 4, 3 (2003)

    Article  Google Scholar 

  40. Huang da. W. Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 44–57 (2009)

    Article  Google Scholar 

  41. Liu, X. S., Brutlag, D. L. & Liu, J. S. An algorithm for finding protein-DNA binding sites with applications to chromatin-immunoprecipitation microarray experiments. Nature Biotechnol. 20, 835–839 (2002)

    Article  CAS  Google Scholar 

  42. Mahony, S. & Benos, P. V. STAMP: a web tool for exploring DNA-binding motif similarities. Nucleic Acids Res. 35, W253–W258 (2007)

    Article  Google Scholar 

Download references

Acknowledgements

We thank M. Snyder and colleagues for high-throughput sequencing (conducted as part of the ENCODE consortium), and members of the Chua and Gozani laboratories for discussions and comments on the manuscript. This work was supported by grants from the National Institutes of Health (NIH) to K.F.C. (K08 AG028961, R01 AG028867), W.L. (U01DA025956), O.G. (R01 GM079641), K.S. (GM 30186, HG 4558) and B.A.G. (DP2OD007447); from the National Science Foundation to B.A.G. (CAREER Award, CBET-0941143); from the Department of Defense to W.L. (PC094421); from the Cancer Prevention and Research Institute of Texas (CPRIT) to W.L. (RP110471-C3); from the Department of Veterans Affairs to K.F.C. (Merit Award); and by fellowship awards to M.F.B. (ARCS Scholarship and Mason Case Graduate Fellowship), R.I.T. (NIH training grant 1018438-142 PABCA), L.T. (American Italian Cancer Foundation Post-doctoral Research Fellowship), S.P. (NIH training grant 3T32DK007217-36S1) and N.L.Y. (NIH F32 NRSA). W.L. is a recipient of a Duncan Scholar Award. K.F.C. is a Paul Beeson Scholar and an Ellison Medical Foundation New Scholar in Aging.

Author information

Author notes

  1. Matthew F. Barber, Eriko Michishita-Kioi & Mitomu Kioi

    Present address: Present addresses: Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA (M.F.B.); R&D Division, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo 140-8710, Japan (E.M.-K.); Department of Oral and Maxillofacial Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan (M.K.).,

  2. Matthew F. Barber, Eriko Michishita-Kioi and Yuanxin Xi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology, Stanford University, Stanford, California 94305, USA,

    Matthew F. Barber & Or Gozani

  2. Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University, Stanford, California 94305, USA,

    Matthew F. Barber, Eriko Michishita-Kioi, Luisa Tasselli, Ruth I. Tennen, Silvana Paredes & Katrin F. Chua

  3. Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California 94304, USA ,

    Eriko Michishita-Kioi, Luisa Tasselli, Silvana Paredes & Katrin F. Chua

  4. Division of Biostatistics, Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA,

    Yuanxin Xi, Kaifu Chen & Wei Li

  5. Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA,

    Mitomu Kioi

  6. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Zarmik Moqtaderi & Kevin Struhl

  7. Cancer Biology Program, Stanford University, Stanford, California 94305, USA ,

    Ruth I. Tennen & Katrin F. Chua

  8. Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA,

    Nicolas L. Young & Benjamin A. Garcia

Authors
  1. Matthew F. Barber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eriko Michishita-Kioi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuanxin Xi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luisa Tasselli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mitomu Kioi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zarmik Moqtaderi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ruth I. Tennen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Silvana Paredes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nicolas L. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kaifu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kevin Struhl
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Benjamin A. Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Or Gozani
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Wei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Katrin F. Chua
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.F.B. and K.F.C. conceived the project and, with E.M.-K. and O.G., designed the experiments. M.F.B. and E.M.-K. performed and interpreted molecular and cell biology experiments, and M.F.B. and K.F.C. wrote the manuscript with input from co-authors. Y.X., K.C. and W.L. performed the bioinformatic analyses and wrote the corresponding manuscript sections. Z.M. and K.S. designed and performed the SIRT7 ChIP-sequencing experiments. L.T. performed and interpreted the experiments in Supplementary Fig. 17; B.A.G. and N.L.Y. performed the quantitative mass spectrometry in Fig. 1g; M.K. performed the mouse xenograft experiments in Fig. 4; R.I.T. and S.P. generated constructs for various experiments and provided technical assistance. M.F.B., E.M.-K. and Y.X. made independent contributions to the work.

Corresponding authors

Correspondence to Wei Li or Katrin F. Chua.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-20 and Supplementary Tables 1 and 4-8 (see separate files for Tables 2, 3 and 9). (PDF 1389 kb)

Supplementary Table 2

This table contains SIRT7 ChIP-seq peak list with annotated genes. The peaks were called by MACS with p-value cut-off 1e-8. (XLS 51 kb)

Supplementary Table 3

This table contains SIRT7 ChIP-seq target gene list. The target genes were identified by detecting SIRT7 peaks within 3Kbp upstream to 3Kbp downtream of transcription start sites (TSS). (XLS 67 kb)

Supplementary Table 9

This table contains ELK4 ChIP-seq peak list with annotated genes. The raw reads were obtained from O'Geen and Lin et al, BMC Genomics 2010, 11:689 (GSE24685), and were remapped to hg18 genome. The peaks were called by MACS with p-value cut-off 1e-8. The target genes were identified by detecting ELK4 peaks within 3Kbp upstream to 3Kbp downtream of transcription start sites (TSS). (XLS 216 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barber, M., Michishita-Kioi, E., Xi, Y. et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 487, 114–118 (2012). https://doi.org/10.1038/nature11043

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11043

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer