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.

  • Original Article
  • Published:

The male-specific factor Sry harbors an oncogenic function

Oncogene volume 33, pages 2978–2986 (2014)Cite this article

Subjects

Abstract

Sgf29, a component of the SPT-ADA-GCN5 acetyltransferase (SAGA) complex, binds H3K4me2/3 marks and leads to histone H3 acetylation. Previously, we found that downregulation of Sgf29 suppresses c-Myc-mediated malignant transformation. Nonetheless, the upstream regulator of the Sgf29 gene is not yet known. Here, we report that Sry (sex-determining region Y), an HMG (high-mobility group) domain containing transcription factor, directly upregulates Sgf29 gene expression. Sry expression was deregulated in two out of the four tested male rodent hepatocellular carcinoma (rHCC) cell lines. Luciferase reporter and chromatin immunoprecipitation assays indicated that Sry could bind HMG-boxes in the proximal promoter region of the Sgf29 gene. Knockdown of Sry robustly lowered anchorage-independent growth, invasiveness and tumorigenicity of rHCC cells, whereas ectopic expression of Sry conferred more malignant properties. Thus, these data show that Sry is involved in male-specific malignant conversion of rHCCs via Sgf29 upregulation.

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
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Kaposi- Noval P, Libbrecht L, Woo H, Lee Y-H, Sears NC, Conner EA et al. Central role of c-Myc during malignant conversion in human hepatocarcinogenesis. Cancer Res 2009; 69: 2775–2782.

    Article  Google Scholar 

  2. Amati B, Frank SR, Donjerkovic D, Taubert S . Function of the c-Myc oncoprotein in chromatin remodeling and transcription. Biochim Biophys Acta 2001; 1471: M135–M145.

    CAS  PubMed  Google Scholar 

  3. Lüscher B . Function and regulation of the transcription factors of the Myc/Max/Mad network. Gene 2001; 277: 1–14.

    Article  Google Scholar 

  4. McMahon SB, Van Buskirk HA, Dugan KA, Copeland TD, Cole MD . The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell 1998; 94: 363–374.

    Article  CAS  Google Scholar 

  5. McMahon SB, Wood MA, Cole MD . The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol Cell Biol 2000; 20: 556–562.

    Article  CAS  Google Scholar 

  6. Park J, Kunjibettu S, McMahon SB, Cole MD . The ATM-related domain of TRRAP is required for histone acetyltransferase recruitment and Myc-dependent oncogenesis. Genes Dev 2001; 15: 1619–1624.

    Article  CAS  Google Scholar 

  7. Lee KK, Workman JL . Histone acetyltransferase complexes: one size doesn’t fit all. Nat Rev Mol Cell Biol 2007; 8: 284–295.

    Article  CAS  Google Scholar 

  8. Vermeulen M, Eberl HC, Matarese F, Marks H, Denissov S, Butter F et al. Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. Cell 2010; 142: 967–980.

    Article  CAS  Google Scholar 

  9. Bian C, Xu C, Ruan J, Lee KK, Burke TL, Tempel W et al. Sgf29 binds histone H3K4me2/3 and is required for SAGA complex recruitment and histone H3 acetylation. EMBO J 2011; 30: 2829–2842.

    Article  CAS  Google Scholar 

  10. Kurabe N, Katagiri K, Komiya Y, Ito R, Sugiyama A, Kawasaki Y et al. Deregulated expression of a novel component of TFTC/STAGA histone acetyltransferase complexes, rat SGF29, in hepatocellular carcinoma: possible implication for the oncogenic potential of c-Myc. Oncogene 2007; 26: 5626–5634.

    Article  CAS  Google Scholar 

  11. Lefebvre V, Dumitriu B, Penzo-Mendez A, Han Y, Pallavi B . Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. Int J Biochem Cell Biol 2007; 39: 2195–2214.

    Article  CAS  Google Scholar 

  12. Phillips NB, Jancso-Radek A, Ittah V, Singh R, Chan G, Haas E et al. SRY and human sex determination: the basic tail of the HMG box functions as a kinetic clamp to augment DNA bending. J Mol Biol 2006; 358: 172–192.

    Article  CAS  Google Scholar 

  13. Nishino K, Hattori N, Tanaka S, Shiota K . DNA methylation-mediated control of Sry gene expression in mouse gonadal development. J Biol Chem 2004; 279: 22306–22313.

    Article  CAS  Google Scholar 

  14. Albrecht KH, Eicher EM . Evidence that Sry is expressed in pre-Sertoli cells and Sertoli and granulosa cells have a common precursor. Dev Biol 2001; 240: 92–107.

    Article  CAS  Google Scholar 

  15. Bullejos M, Koopman P . Spatially dynamic expression of Sry in mouse genital ridges. Dev Dyn 2001; 221: 201–205.

    Article  CAS  Google Scholar 

  16. Sekido R, Lovell-Badge R . Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 2008; 453: 930–934.

    Article  CAS  Google Scholar 

  17. Sugiyama A, Miyagi Y, Komiya Y, Kurabe N, Kitanaka C, Kato N et al. Forced expression of antisense 14-3-3 beta RNA suppresses tumor growth in vivo and vivo. Carcinogenesis 2003; 24: 1549–1559.

    Article  CAS  Google Scholar 

  18. Komiya Y, Kurabe N, Katagiri K, Ogawa M, Sugiyama A, Kawasaki Y et al. A novel binding factor of 14-3-3beta functions as a transcriptional repressor and promotes anchorage-independent growth, tumorigenicity, and metastasis. J Biol Chem 2008; 283: 18753–18764.

    Article  CAS  Google Scholar 

  19. Mattheews V, Tanaka K, Driacoll J, Ichikawa A, Goldberg A . Involvement of the proteasome in various degaradation processes in mammalian cells. Proc Nat Acad Sci USA 1989; 86: 2597–2601.

    Article  Google Scholar 

  20. Kawasaki Y, Adachi N, Yamazaki T, Todoroki R, Gotou Y, Komiya Y et al. Cancer stem cells in aflatoxin B1-induced rat hepatocellular carcinoma K2 cells. Mycotoxins 2007; 57: 87–93.

    Article  CAS  Google Scholar 

  21. Murray JD, Braithwaite AW, Taylor IW, Bellett AJD . Adenovirus-induced alteration of the cell growth cycle: effects of mutation in early regions E1A and E2B. J Virol 1982; 44: 1072–1075.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Katoh H, Ojima H, Saito S, Kondo T, Hosoda F, Imoto I et al. Genetically distinct and clinically relevant classification of hepatocellular carcinoma: putative therapeutic targets. Gastroenterology 2007; 133: 1475–1486.

    Article  CAS  Google Scholar 

  23. Iyengar RV, Pawlik CA, Krull EJ, Phelps DA, Burger RA, Harris LC et al. Use of a modified ornithine decarboxylase promoter to achieve efficient c-MYC- or N-MYC-regulated protein expression. Cancer Res 2001; 61: 3045–3052.

    CAS  PubMed  Google Scholar 

  24. Nilsson JA, Keller UB, Baudino TA, Yang C, Norton S, Old JA et al. Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation. Cancer Cell 2005; 7: 433–444.

    Article  CAS  Google Scholar 

  25. Zhang XY, DeSalle LM, Patel JH, Capobianco AJ, Yu D, Thomas-Tikhonenko A et al. Metastasis-associated protein 1 (MTA1) is an essential downstream effector of the c-MYC oncoprotein. Proc Natl Acad Sci USA 2005; 102: 13968–13973.

    Article  CAS  Google Scholar 

  26. Palaskas N, Larson SM, Schultz N, Komisopoulou E, Wong J et al. 18F-Fluorodeoxy-glucose positron emission tomography marks Myc-overexpressing human basal-like breast cancers. Cancer Res 2011; 71: 5164–5174.

    Article  CAS  Google Scholar 

  27. Liu L, Ulbrich J, WÜstefeld T, Aeberhard L, Kress TR, Muthalagu N et al. Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature 2012; 483: 608–612.

    Article  CAS  Google Scholar 

  28. Bradford ST, Wilhelm D, Bandiera R, Vidal V, Schedl A, Koopman P . A cell-autonomous role for WT1 in regulating Sry in vivo. Hum Mol Genet 2009; 18: 3429–3438.

    Article  CAS  Google Scholar 

  29. Ling S, Chang X, Schultz L, Lee TK, Chaux A, Marchionni L et al. An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer. Cancer Res 2011; 71: 3812–3821.

    Article  CAS  Google Scholar 

  30. Thomsen MK, Ambroisine L, Wynn S, Cheah KS, Foster CS et al. SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation. Cancer Res 2010; 70: 979–987.

    Article  CAS  Google Scholar 

  31. Clevers H . The cancer stem cell: premises, promises and challenges. Nat Med 2011; 17: 313–319.

    Article  CAS  Google Scholar 

  32. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645–648.

    Article  CAS  Google Scholar 

  33. Reya T, Morrison SJ, Clarke MF, Weissman IL . Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–111.

    Article  CAS  Google Scholar 

  34. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.

    Article  CAS  Google Scholar 

  35. Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB . Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 2009; 8: 806–823.

    Article  CAS  Google Scholar 

  36. Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663–676.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to K Katagiri for the technical assistance. This work was partly supported by the ‘Academic Frontier’ project for Private University: a matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology), 2006–2010 (to FT) and 2010–2012 (to HA).

Author information

Authors and Affiliations

  1. Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan

    S Murakami, S Chishima, H Uemoto, E Sakamoto, T Sato, N Kurabe, Y Kawasaki, H Akiyama & F Tashiro

  2. Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan

    T Shibata

Authors
  1. S Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Chishima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Uemoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N Kurabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y Kawasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H Akiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F Tashiro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Tashiro.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Murakami, S., Chishima, S., Uemoto, H. et al. The male-specific factor Sry harbors an oncogenic function. Oncogene 33, 2978–2986 (2014). https://doi.org/10.1038/onc.2013.262

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.262

Keywords

Search

Advanced search

Quick links