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:

UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression

Oncogene volume 31, pages 5061–5072 (2012)Cite this article

Subjects

Abstract

Peroxisome proliferator-activated receptor gamma (PPARG) inactivation has been identified as an important step in colorectal cancer (CRC) progression, although the events involved have been partially clarified. UHRF1 is emerging as a cofactor that coordinates the epigenetic silencing of tumor suppressor genes, but its role in CRC remains elusive. Here, we report that UHRF1 negatively regulates PPARG and is associated with a higher proliferative, clonogenic and migration potential. Consistently, UHRF1 ectopic expression induces PPARG repression through its recruitment on the PPARG promoter fostering DNA methylation and histone repressive modifications. In agreement, UHRF1 knockdown elicits PPARG re-activation, accompanied by positive histone marks and DNA demethylation, corroborating its role in PPARG silencing. UHRF1 overexpression, as well as PPARG-silencing, imparts higher growth rate and phenotypic features resembling those occurring in the epithelial-mesenchymal transition. In our series of 110 sporadic CRCs, high UHRF1-expressing tumors are characterized by an undifferentiated phenotype, higher proliferation rate and poor clinical outcome only in advanced stages III–IV. In addition, the inverse relationship with PPARG found in vitro is detected in vivo and UHRF1 prognostic significance appears closely related to PPARG low expression, as remarkably validated in an independent dataset. The results demonstrate that UHRF1 regulates PPARG silencing and both genes appear to be part of a complex regulatory network. These findings suggest that the relationship between UHRF1 and PPARG may have a relevant role in CRC progression.

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
Figure 7

Similar content being viewed by others

References

  • Alhosin M, Sharif T, Mousli M, Etienne-Selloum N, Fuhrmann G, Schini-Kerth VB et al. (2011). Down-regulation of UHRF1, associated with re-expression of tumor suppressor genes, is a common feature of natural compounds exhibiting anti-cancer properties. J Exp Clin Cancer Res 15: 30–41.

    Google Scholar 

  • Babbio F, Pistore C, Curti L, Castiglioni I, Paolo K, Brino L et al. (2011). The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression. Oncogene 31: 4878–4887.

    Article  Google Scholar 

  • Bostick M, Kim JK, Esteve PO, Clark A, Pradhan S, Jacobsen SE . (2007). UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317: 1760–1764.

    Article  CAS  PubMed  Google Scholar 

  • Bruna A, Darken RS, Rojo F, Ocaña A, Peñuelas S, Arias A et al. (2007). High TGFb-Smad Activity Confers Poor Prognosis in Glioma Patients and Promotes Cell Proliferation Depending on the Methylationof the PDGF-B Gene. CancerCell 11: 147–160.

    CAS  Google Scholar 

  • Burchill SA, Bradbury MF, Pittman K, Southgate J, Smith B, Selby P . (1995). Detection of epithelial cancer cells in peripheral blood by reverse transcriptase-polymerase chain reaction. Br J Cancer 71: 278–281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Capaccio D, Ciccodicola A, Sabatino L, Casamassini A, Pancione M, Fucci A et al. (2010). A novel germline mutation in Peroxisome Proliferator-Activated Receptor γ gene associated with large intestine polyp formation and dyslipidemia. Biochim Biophys Acta 1802: 572–581.

    Article  CAS  PubMed  Google Scholar 

  • Cheng X, Blumenthal RM . (2010). Coordinated chromatin control: structural and functional linkage of DNA and histone methylation. Biochemistry 49: 2999–3008.

    Article  CAS  PubMed  Google Scholar 

  • Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W . (2006). From molecular action to physiological outputs: Peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res 45: 120–159.

    Article  CAS  PubMed  Google Scholar 

  • Füllgrabe J, Kavanagh E, Joseph B . (2011). Histone oncomodifications. Oncogene 30: 3391–3403.

    Article  PubMed  Google Scholar 

  • Grommes C, Landreth G, Heneka MT . (2004). Antineoplastic effects of peroxisome proliferator activated receptor γ agonists. Lancet Oncol 7: 419–429.

    Article  Google Scholar 

  • Hayashi K, Yokozaki H, Naka K, Yasui W, Lotan R, Tahara E . (2001). Overexpression of retinoic acid receptor β induces growth arrest and apoptosis in oral cancer cell lines. Jpn J Cancer Res 92: 42–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ibrahim AE, Arends MJ, Silva AL, Wyllie AH, Greger L, Ito Y et al. (2011). Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression. Gut 60: 444–508.

    Article  Google Scholar 

  • Issa JP . (2004). CpG island methylator phenotype in cancer. Nat Rev Cancer 4: 988–993.

    Article  CAS  PubMed  Google Scholar 

  • Jones PA, Baylin SB . (2007). The epigenomics of cancer. Cell 128: 683–692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim KJ, Esteve1 PO, Jacobsen SE, Pradhan S . (2009). UHRF1 binds G9a and participates in p21 transcriptional regulation in mammalian cells. Nucleic Acids Res 37: 493–505.

    Article  CAS  PubMed  Google Scholar 

  • Knouff C, Auwerx J . (2004). Peroxisome proliferator-activated receptor-γ calls for activation in moderation: lessons from genetics and pharmacology. Endocrine Rev 25: 899–918.

    Article  CAS  Google Scholar 

  • Kondo Y, Shen L, Cheng AS, Ahmed S, Boumber Y, Charo C et al. (2008). Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet 40: 741–750.

    Article  CAS  PubMed  Google Scholar 

  • Kouzarides T . (2007). Chromatin modifications and their function. Cell 128: 693–705.

    Article  CAS  PubMed  Google Scholar 

  • Kumar A, Xu J, Brady S, Gao H, Yu D, Reuben J et al. (2010). Tissue transglutaminase promotes drug resistance and invasion by inducing mesenchymal transition in mammary epithelial cells. PlosOne 5: e13390.

    Article  Google Scholar 

  • Linhart HG, Lin H, Yamada Y, Moran E, Steine EJ, Gokhale S et al. (2007). Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev 21: 3110–3122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lorenzato M, Caudroy S, Bronner C, Evrard G, Simon M, Durlach A et al. (2005). Cell cycle and/or proliferation markers: what is the best method to discriminate cervical high-grade lesions? Hum Pathol 36: 1101–1107.

    Article  CAS  PubMed  Google Scholar 

  • McCabe MT, Brandes JC, Vertino PM . (2009). Cancer DNA methylation: molecular mechanisms and clinical implications. Clin Cancer Res 15: 3927–3937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meilinger D, Fellinger K . (2009). Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells. EMBO Rep 10: 1259–1264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakazawa T, Kondo T, Ma D, Niu D, Mochizuki K, Kawasaki T et al. (2011). Global histone modification of histone H3 in colorectal cancer and its precursor lesions. Hum Pathol (e-pub ahead of print 13 September 2011).

  • Nosho K, Shima K, Irahara N, Kure S, Baba Y, Kirkner GJ et al. (2009). DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer. Clin Cancer Res 15: 3663–3671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ogino S, Shima K, Baba Y, Nosho K, Irahara N, Kure S et al. (2009). Colorectal cancer expression of PPARG (Peroxisome Proliferator-Activated Receptor-γ) is associated with good prognosis. Gastroenterology 136: 1242–1250.

    Article  CAS  PubMed  Google Scholar 

  • Pancione M, Forte N, Fucci A, Sabatino L, Febbraro A, Di Blasi A et al. (2010a). Prognostic role of β-catenin and p53 expression in the metastatic progression of sporadic colorectal cancer. Hum Pathol 41: 867–876.

    Article  CAS  PubMed  Google Scholar 

  • Pancione M, Sabatino L, Fucci A, Carafa V, Nebbioso A, Forte N et al. (2010b). Epigenetic silencing of Peroxisome Proliferator-Activated Receptor γ is a biomarker for colorectal cancer progression and adverse patients’ outcome. PlosOne 5: e14229.

    Article  CAS  Google Scholar 

  • Papait R, Pistore C, Negri D, Pecoraro D, Cantarini L, Bonapace IM . (2007). Np95 is implicated in pericentromeric heterochromatin replication and in major satellite silencing. Mol Biol Cell 18: 1098–1106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Phe V, Cussenot O, Roupret M . (2010). Methylated genes as potential biomarkers in prostate cancer. Br J Urol Int 105: 1364–1370.

    Article  CAS  Google Scholar 

  • Portela A, Esteller M . (2010). Epigenetic modifications and human disease. Nat Biotechnol 28: 1057–1068.

    Article  CAS  PubMed  Google Scholar 

  • Sabatino L, Casamassimi A, Peluso G, Barone MV, Capaccio D, Migliore C et al. (2005). A novel peroxisome proliferator-activated receptor γ isoform with dominant negative activity generated by alternative splicing. J Biol Chem 280: 26517–26525.

    Article  CAS  PubMed  Google Scholar 

  • Sarraf P, Mueller E, Smith WM, Wright HM, Kum JB, Aaltonen LA et al. (1999). Loss-of-function mutations in PPARγ associated with human colon cancer. Mol Cell 3: 799–804.

    Article  CAS  PubMed  Google Scholar 

  • Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo TA et al. (2007). The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450: 908–912.

    Article  CAS  PubMed  Google Scholar 

  • Shen CX, Hu Lh, Li YR . (2008). Quantitative Real Time RT-PCR detection for survivin, CK20 and CEA in peripheral blood of colorectal cancer patients. JPN J Clin Oncol 38: 770–776.

    Article  PubMed  Google Scholar 

  • Smith JJ, Deane NG, Wu F, Merchant NB, Zhang B, Jiang A et al. (2010). Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer. Gastroenterology 138: 958–968.

    Article  CAS  PubMed  Google Scholar 

  • Tien AL, Senbanerjee S, Kulkarni A . (2011). UHRF1 depletion causes a G2/M arrest, activation of DNA damage response and apoptosis. Biochem J 435: 175–185.

    Article  CAS  PubMed  Google Scholar 

  • Unoki M, Nishidate T, Nakamura Y . (2004). ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene 23: 7601–7610.

    Article  CAS  PubMed  Google Scholar 

  • Varier HT, Timmers M . (2011). Histone lysine methylation and demethylation pathways in cancer. Biochimica et Biophysica Acta 1815: 75–89.

    CAS  PubMed  Google Scholar 

  • Wang D, Dubois RN . (2008). Peroxisome proliferator-activated receptors and progression of colorectal cancer. PPAR Res 2008: 931074.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) to LA and IMB; Fondazione Cariplo ‘Progetto Nobel’ to IMB; European Union: CancerDip contract no 200620, Aposys contract no 200767 to LA; Associazione Italiana per la lotta ai linfomi e leucemie (AIL) to VC. We wish to thank Prof N Zambrano for kindly providing the shRNA vectors employed.

Author information

Author notes

  1. L Sabatino and A Fucci: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological, Geological and Environmental Sciences, University of Sannio, Benevento, Italy

    L Sabatino, A Fucci, M Pancione, C Votino, C Laudanna, M Ceccarelli & V Colantuoni

  2. Department of General Pathology, II University of Naples, Naples, Italy

    V Carafa, A Nebbioso & L Altucci

  3. Department of Structural and Functional Biology, University of Insubria, Busto Arsizio (Va), Italy

    C Pistore, F Babbio & I M Bonapace

Authors
  1. L Sabatino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Fucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Pancione
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V Carafa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Nebbioso
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Pistore
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F Babbio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C Votino
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C Laudanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Ceccarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L Altucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. I M Bonapace
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. V Colantuoni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V Colantuoni.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sabatino, L., Fucci, A., Pancione, M. et al. UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression. Oncogene 31, 5061–5072 (2012). https://doi.org/10.1038/onc.2012.3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.3

Keywords

This article is cited by

Search

Advanced search

Quick links