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.

  • Article
  • Published:

Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin

Nature Cell Biology volume 14, pages 1203–1211 (2012)Cite this article

Subjects

A Corrigendum to this article was published on 02 April 2013

This article has been updated

Abstract

Understanding stage-dependent oncogenic mechanisms is critical to develop not only targeted therapies, but also diagnostic markers and preventive strategies. The mechanisms acting during cancer initiation remain elusive, largely owing to a lack of suitable animal models and limited availability of human precancerous lesions. Here we show using genetic mouse models specific for liver cancer initiation, that survival of initiated cancer cells is controlled by c-Jun, independently of p53, through suppressing c-Fos-mediated apoptosis. Mechanistically, c-Fos induces SIRT6 transcription, which represses survivin by reducing histone H3K9 acetylation and NF-κB activation. Importantly, increasing the level of SIRT6 or targeting the anti-apoptotic activity of survivin at the initiation stage markedly impairs cancer development. Moreover, in human dysplastic liver nodules, but not in malignant tumours, a specific expression pattern with increased c-Jun–survivin and attenuated c-Fos–SIRT6 levels was identified. These results reveal a regulatory network connecting stress response and histone modification in liver tumour initiation, which could be targeted to prevent liver tumorigenesis.

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: c-Jun-dependent cell survival during liver cancer initiation.
Figure 2: Survivin promotes cell survival during liver cancer initiation.
Figure 3: Impaired SIRT6 expression in c-Jun-deficient livers during tumour initiation.
Figure 4: SIRT6 enhances DEN-induced cell death by repressing survivin.
Figure 5: c-Fos enhances SIRT6 transcription during liver cancer initiation.
Figure 6: c-Fos causes reduced cancer initiation in livers lacking c-Jun.
Figure 7: Interfering with liver cancer initiation impairs long-term tumorigenesis.
Figure 8: AP-1-dependent regulatory network during human liver cancer initiation.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Change history

  • 14 March 2013

    A correction has been made to a sentence in the section "Interfering with liver cancer initiation prevents tumorigenesis". A correction to Fig. 8c and further clarification of Figs 1a, 2b, 3d, 4c and 4g can be found in the accompanying Corrigendum.

References

  1. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  Google Scholar 

  2. Gotay, C. C. Cancer prevention: major initiatives and looking into the future. Exp. Rev. Pharmacoecon Outcomes Res. 10, 143–154 (2010).

    Article  Google Scholar 

  3. Farazi, P. A. & DePinho, R. A. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat. Rev. Cancer 6, 674–687 (2006).

    Article  CAS  Google Scholar 

  4. Poon, R. T. Prevention of recurrence after resection of hepatocellular carcinoma: a daunting challenge. Hepatology 54, 757–759 (2011).

    Article  Google Scholar 

  5. He, G. et al. Hepatocyte IKKβ/NF-κB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17, 286–297 (2010).

    Article  CAS  Google Scholar 

  6. Takami, T. et al. Loss of hepatocyte growth factor/c-Met signaling pathway accelerates early stages of N-nitrosodiethylamine induced hepatocarcinogenesis. Cancer Res. 67, 9844–9851 (2007).

    Article  CAS  Google Scholar 

  7. Maeda, S., Kamata, H., Luo, J. L., Leffert, H. & Karin, M. IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990 (2005).

    Article  CAS  Google Scholar 

  8. Eferl, R. & Wagner, E. F. AP-1: a double-edged sword in tumorigenesis. Nat. Rev. Cancer 3, 859–868 (2003).

    Article  CAS  Google Scholar 

  9. Lopez-Bergami, P., Lau, E. & Ronai, Z. Emerging roles of ATF2 and the dynamic AP1 network in cancer. Nat. Rev. Cancer 10, 65–76 (2010).

    Article  CAS  Google Scholar 

  10. Lee, J. S. et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nature Med. 12, 410–416 (2006).

    Article  CAS  Google Scholar 

  11. Eferl, R. et al. Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell 112, 181–192 (2003).

    Article  CAS  Google Scholar 

  12. Hui, L., Zatloukal, K., Scheuch, H., Stepniak, E. & Wagner, E. F. Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J. Clin. Invest. 118, 3943–3953 (2008).

    Article  CAS  Google Scholar 

  13. Hui, L. et al. p38α suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat. Genet 39, 741–749 (2007).

    Article  CAS  Google Scholar 

  14. Das, M., Garlick, D. S., Greiner, D. L. & Davis, R. J. The role of JNK in the development of hepatocellular carcinoma. Gene. Dev. 25, 634–645 (2011).

    Article  CAS  Google Scholar 

  15. Hasselblatt, P., Rath, M., Komnenovic, V., Zatloukal, K. & Wagner, E. F. Hepatocyte survival in acute hepatitis is due to c-Jun/AP-1-dependent expression of inducible nitric oxide synthase. Proc. Natl Acad. Sci. USA 104, 17105–17110 (2007).

    Article  CAS  Google Scholar 

  16. Liu, P. et al. Activation of NF-κB, AP-1 and STAT transcription factors is afrequent and early event in human hepatocellular carcinomas. J. Hepatol. 37, 63–71 (2002).

    Article  Google Scholar 

  17. Fausto, N. & Campbell, J. S. Mouse models of hepatocellular carcinoma. Semin. Liver Dis. 30, 87–98 (2010).

    Article  CAS  Google Scholar 

  18. Kellendonk, C., Opherk, C., Anlag, K., Schutz, G. & Tronche, F. Hepatocyte-specific expression of Cre recombinase. Genesis 26, 151–153 (2000).

    Article  CAS  Google Scholar 

  19. Ramachandran, R. & Kakar, S. Histological patterns in drug-induced liver disease. J. Clin. Pathol. 62, 481–492 (2009).

    Article  CAS  Google Scholar 

  20. Altieri, D. C. Survivin, cancer networks and pathway-directed drug discovery. Nat. Rev. Cancer 8, 61–70 (2008).

    Article  CAS  Google Scholar 

  21. Kinoshita, K. et al. Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats. Gut 56, 706–714 (2007).

    Article  CAS  Google Scholar 

  22. Mesri, M., Wall, N. R., Li, J., Kim, R. W. & Altieri, D. C. Cancer gene therapy using a survivin mutant adenovirus. J. Clin. Invest. 108, 981–990 (2001).

    Article  CAS  Google Scholar 

  23. Wang, R. H. et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol. Cell 32, 11–20 (2008).

    Article  Google Scholar 

  24. Kawahara, T. L. et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-κB-dependent gene expression and organismal life span. Cell 136, 62–74 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Bozec, A. et al. Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. Nature 454, 221–225 (2008).

    Article  CAS  Google Scholar 

  27. Mehic, D., Bakiri, L., Ghannadan, M., Wagner, E. F. & Tschachler, E. Fos and jun proteins are specifically expressed during differentiation of human keratinocytes. J. Invest. Dermatol. 124, 212–220 (2005).

    Article  CAS  Google Scholar 

  28. Goto, H. et al. Complex formation of Plk1 and INCENP required for metaphase–anaphase transition. Nat. Cell Biol. 8, 180–187 (2006).

    Article  CAS  Google Scholar 

  29. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 49 658–664 (2009).

  30. Reed, K. R. et al. A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine. BMC Cancer 8, 162 (2008).

    Article  Google Scholar 

  31. Christophorou, M. A., Ringshausen, I., Finch, A. J., Swigart, L. B. & Evan, G. I. The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443, 214–217 (2006).

    Article  CAS  Google Scholar 

  32. Feldser, D. M. et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 468, 572–575 (2010).

    Article  CAS  Google Scholar 

  33. Junttila, M. R. et al. Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature 468, 567–571 (2010).

    Article  CAS  Google Scholar 

  34. Pikarsky, E. et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).

    Article  CAS  Google Scholar 

  35. Meixner, A., Karreth, F., Kenner, L., Penninger, J. M. & Wagner, E. F. Jun and JunD-dependent functions in cell proliferation and stress response. Cell. Death Differ. (2010).

  36. Mikula, M. et al. The proto-oncoprotein c-Fos negatively regulates hepatocellular tumorigenesis. Oncogene 22, 6725–6738 (2003).

    Article  CAS  Google Scholar 

  37. Fleischmann, A., Jochum, W., Eferl, R., Witowsky, J. & Wagner, E. F. Rhabdomyosarcoma development in mice lacking Trp53 and Fos: tumor suppression by the Fos protooncogene. Cancer Cell 4, 477–482 (2003).

    Article  CAS  Google Scholar 

  38. Montorsi, M. et al. Survivin gene expression in chronic liver disease and hepatocellular carcinoma. Hepatogastroenterology 54, 2040–2044 (2007).

    PubMed  Google Scholar 

  39. Kim, H. S. et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab. 12, 224–236 (2010).

    Article  CAS  Google Scholar 

  40. Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was initiated at the Research Institute of Molecular Pathology, which is funded by Boehringer Ingelheim. We thank S. Ji for technical support and R. Eferl, P. Hasselblatt, M. Sibilia, P. Angel and J. Hess for critical reading of the manuscript. We are also grateful to D. Altieri (University of Massachusetts, USA) for survivin and SurT34A adenoviruses, K. Chua (Stanford University, USA) for SIRT6 and SIRT6HY plasmids, M. F. Rajewsky (University of Essen, Germany) for antibodies against DNA adducts, and the Biobank of the Medical University of Graz, Austria for providing further human liver samples. Work in the L.H. laboratory is funded by the National Science Foundation of China (31071238), the Ministry of Science and Technology of China (2012CB945001, 2011ZX09307-302-01) and the Chinese Academy of Sciences (the Hundred Talents Program). Work in the E.F.W. laboratory is supported by a grant from F-BBVA and an ERC-Advanced grant ERC-FCK/2008/37. K.Z. is supported by the Austrian genome program GEN-AU.

Author information

Authors and Affiliations

  1. State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Yueyang Road 320, Shanghai 200031, China

    Lihua Min, Zhixin Qiu, Jin Cen, Xiaotao Chen, Hai Zheng & Lijian Hui

  2. Department of Pathology, Zhongshan Hospital, Fudan University, Fenglin Road 180, 200032 Shanghai, China

    Yuan Ji & Lingli Chen

  3. Genes, Development and Disease Group, F-BBVA-CNIO Cancer Cell Biology Programme, Spanish National Cancer Research Centre, Melchor Fernandez Almagro 3, 28029 Madrid, Spain

    Latifa Bakiri & Erwin F. Wagner

  4. Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria

    Harald Scheuch

  5. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Fenglin Road 180, 200032 Shanghai, China

    Lunxiu Qin

  6. Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria

    Kurt Zatloukal

Authors
  1. Lihua Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuan Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Latifa Bakiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhixin Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jin Cen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaotao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lingli Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Harald Scheuch
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hai Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lunxiu Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kurt Zatloukal
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lijian Hui
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Erwin F. Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.H., L.B. and E.F.W. designed the project and L.H. analysed early stages of cell death. L.M. characterized the role of survivin, SIRT6 and c-Fos in liver tumour initiation. L.M., Y.J., L.C., L.Q., L.B. and K.Z. analysed human samples. X.C., Z.Q., J.C., Z.H. and H.S. provided technical support on immunohistochemical staining and gene expression analysis. L.H., L.B. and E.F.W. wrote the manuscript.

Corresponding authors

Correspondence to Lijian Hui or Erwin F. Wagner.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 629 kb)

Supplementary Tables 1–9

Supplementary Information (XLS 69 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Min, L., Ji, Y., Bakiri, L. et al. Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. Nat Cell Biol 14, 1203–1211 (2012). https://doi.org/10.1038/ncb2590

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2590

This article is cited by

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