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SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation

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

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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.

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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.

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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/.

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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

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  1. Matthew F. Barber
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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.

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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)

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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

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