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:

SOX15 is a candidate tumor suppressor in pancreatic cancer with a potential role in Wnt/β-catenin signaling

Oncogene volume 33, pages 279–288 (2014)Cite this article

Subjects

Abstract

Pancreatic cancer is among the top five deadliest cancers in developed countries. Better knowledge of the molecular mechanisms contributing to its tumorigenesis is imperative to improve patient prognosis. Identification of novel tumor suppressor genes (TSGs) in pancreatic cancer will reveal new mechanisms of pathway deregulation and will ultimately help improve our understanding of this aggressive disease. According to Knudson’s two-hit model, TSGs are classically disrupted by two concerted genetic events. In this study, we combined DNA methylation profiling with copy number and mRNA expression profiling to identify novel TSGs in a set of 20 pancreatic cancer cell lines. These data sets were integrated for each of ∼12 000 genes in each cell line enabling the elucidation of those genes that undergo DNA hypermethylation, copy-number loss and mRNA downregulation simultaneously in multiple cell lines. Using this integrative genomics strategy, we identified SOX15 (sex determining region Y—box 15) as a candidate TSG in pancreatic cancer. Expression of SOX15 in pancreatic cancer cell lines with undetectable expression resulted in reduced viability of cancer cells both in vitro and in vivo demonstrating its tumor suppressive capability. We also found reduced expression, homozygous deletion and aberrant DNA methylation of SOX15 in clinical pancreatic tumor data sets. Furthermore, we deduced a novel role for SOX15 in suppressing the Wnt/β-catenin signaling pathway, which we hypothesize is a pathway through which SOX15 may exert its tumor suppressive effects in pancreatic cancer.

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

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.

    Article  PubMed  Google Scholar 

  2. Bardeesy N, DePinho RA . Pancreatic cancer biology and genetics. Nat Rev Cancer 2002; 2: 897–909.

    Article  CAS  PubMed  Google Scholar 

  3. Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA . Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006; 20: 1218–1249.

    Article  CAS  PubMed  Google Scholar 

  4. Singh P, Srinivasan R, Wig JD . Major molecular markers in pancreatic ductal adenocarcinoma and their roles in screening, diagnosis, prognosis, and treatment. Pancreas 2011; 40: 644–652.

    Article  PubMed  Google Scholar 

  5. Samuel N, Hudson TJ . The molecular and cellular heterogeneity of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol Hepatol 2012; 9: 77–87.

    Article  CAS  Google Scholar 

  6. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801–1806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mann KM, Ward JM, Yew CC, Kovochich A, Dawson DW, Black MA et al. Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America 2012; 109: 5934–5941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 2011; 331: 1199–1203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wu J, Jiao Y, Dal Molin M, Maitra A, de Wilde RF, Wood LD et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proceedings of the National Academy of Sciences of the United States of America 2011; 108: 21188–21193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Birnbaum DJ, Adelaide J, Mamessier E, Finetti P, Lagarde A, Monges G et al. Genome profiling of pancreatic adenocarcinoma. Genes Chromosomes Cancer 2011; 50: 456–465.

    Article  CAS  PubMed  Google Scholar 

  11. Joergensen MT, Geisz A, Brusgaard K, Schaffalitzky de Muckadell OB, Hegyi P, Gerdes AM et al. Intragenic duplication: a novel mutational mechanism in hereditary pancreatitis. Pancreas 2011; 40: 540–546.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010; 467: 1114–1117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Berger AH, Knudson AG, Pandolfi PP . A continuum model for tumour suppression. Nature 2011; 476: 163–169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bernard P, Harley VR . Acquisition of SOX transcription factor specificity through protein-protein interaction, modulation of Wnt signalling and post-translational modification. Int J Biochem Cell Biol 2010; 42: 400–410.

    Article  CAS  PubMed  Google Scholar 

  15. Tan AC, Jimeno A, Lin SH, Wheelhouse J, Chan F, Solomon A et al. Characterizing DNA methylation patterns in pancreatic cancer genome. Mol Oncol 2009; 3: 425–438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vincent A, Omura N, Hong SM, Jaffe A, Eshleman J, Goggins M . Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma. Clinic Cancer Res 2011; 17: 4341–4354.

    Article  CAS  Google Scholar 

  17. Hong SM, Omura N, Vincent A, Li A, Knight S, Yu J et al. Genome-wide CpG island profiling of intraductal papillary mucinous neoplasms of the pancreas. Clinic Cancer Res 2012; 18: 700–712.

    Article  CAS  Google Scholar 

  18. Du YC, Oshima H, Oguma K, Kitamura T, Itadani H, Fujimura T et al. Induction and down-regulation of Sox17 and its possible roles during the course of gastrointestinal tumorigenesis. Gastroenterology 2009; 137: 1346–1357.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang W, Glockner SC, Guo M, Machida EO, Wang DH, Easwaran H et al. Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer. Cancer Res 2008; 68: 2764–2772.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jia Y, Yang Y, Liu S, Herman JG, Lu F, Guo M . SOX17 antagonizes WNT/beta-catenin signaling pathway in hepatocellular carcinoma. Epigenetics 2010; 5: 743–749.

    Article  CAS  PubMed  Google Scholar 

  21. Sakai M, Hibi K, Koshikawa K, Inoue S, Takeda S, Kaneko T et al. Frequent promoter methylation and gene silencing of CDH13 in pancreatic cancer. Cancer Sci 2004; 95: 588–591.

    Article  CAS  PubMed  Google Scholar 

  22. Andreeva AV, Kutuzov MA . Cadherin 13 in cancer. Genes Chromosomes Cancer 2010; 49: 775–790.

    CAS  PubMed  Google Scholar 

  23. Bachman KE, Herman JG, Corn PG, Merlo A, Costello JF, Cavenee WK et al. Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggest a suppressor role in kidney, brain, and other human cancers. Cancer Res 1999; 59: 798–802.

    CAS  PubMed  Google Scholar 

  24. MacGrogan D, Levy A, Bova GS, Isaacs WB, Bookstein R . Structure and methylation-associated silencing of a gene within a homozygously deleted region of human chromosome band 8p22. Genomics 1996; 35: 55–65.

    Article  CAS  PubMed  Google Scholar 

  25. McCleary-Wheeler AL, McWilliams R, Fernandez-Zapico ME . Aberrant signaling pathways in pancreatic cancer: a two compartment view. Mol Carcinog 2012; 51: 25–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Morris JPt, Wang SC, Hebrok M . KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer 2010; 10: 683–695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pasca di Magliano M, Biankin AV, Heiser PW, Cano DA, Gutierrez PJ, Deramaudt T et al. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PloS one 2007; 2: e1155.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 2004; 36: 417–422.

    Article  CAS  PubMed  Google Scholar 

  29. Suzuki H, Toyota M, Carraway H, Gabrielson E, Ohmura T, Fujikane T et al. Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer. Br J Cancer 2008; 98: 1147–1156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kongkham PN, Northcott PA, Croul SE, Smith CA, Taylor MD, Rutka JT . The SFRP family of WNT inhibitors function as novel tumor suppressor genes epigenetically silenced in medulloblastoma. Oncogene 2010; 29: 3017–3024.

    Article  CAS  PubMed  Google Scholar 

  31. Licchesi JD, Westra WH, Hooker CM, Machida EO, Baylin SB, Herman JG . Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung. Carcinogenesis 2008; 29: 895–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gumz ML, Zou H, Kreinest PA, Childs AC, Belmonte LS, LeGrand SN et al. Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma. Clin Cancer Res 2007; 13: 4740–4749.

    Article  CAS  PubMed  Google Scholar 

  33. Rajan N, Burn J, Langtry J, Sieber-Blum M, Lord CJ, Ashworth A . Transition from cylindroma to spiradenoma in CYLD-defective tumours is associated with reduced DKK2 expression. J Pathol 2011; 224: 309–321.

    Article  CAS  PubMed  Google Scholar 

  34. Sato H, Suzuki H, Toyota M, Nojima M, Maruyama R, Sasaki S et al. Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. Carcinogenesis 2007; 28: 2459–2466.

    Article  CAS  PubMed  Google Scholar 

  35. Tennis MA, Vanscoyk M, Freeman S, Winn RA . Promoter hypermethylation leads to loss of wnt7a in non-small cell lung cancer. Proceedings of the American Thoracic Society 2012; 9: 83–84.

    Article  Google Scholar 

  36. Tennis MA, Vanscoyk MM, Wilson LA, Kelley N, Winn RA . Methylation of Wnt7a is modulated by dnmt1 and cigarette smoke condensate in non-small cell lung cancer. PloS one 2012; 7: e32921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rubin JS, Barshishat-Kupper M, Feroze-Merzoug F, Xi ZF . Secreted WNT antagonists as tumor suppressors: pro and con. Front Biosci 2006; 11: 2093–2105.

    Article  CAS  PubMed  Google Scholar 

  38. Qin YR, Tang H, Xie F, Liu H, Zhu Y, Ai J et al. Characterization of tumor-suppressive function of SOX6 in human esophageal squamous cell carcinoma. Clinic Cancer Res 2011; 17: 46–55.

    Article  CAS  Google Scholar 

  39. Ye YW, Wu JH, Wang CM, Zhou Y, Du CY, Zheng BQ et al. Sox17 regulates proliferation and cell cycle during gastric cancer progression. Cancer Lett 2011; 307: 124–131.

    Article  CAS  PubMed  Google Scholar 

  40. Kormish JD, Sinner D, Zorn AM . Interactions between SOX factors and Wnt/beta-catenin signaling in development and disease. Dev Dyn 2010; 239: 56–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. van Noort M, Meeldijk J, van der Zee R, Destree O, Clevers H . Wnt signaling controls the phosphorylation status of beta-catenin. J Biol Chem 2002; 277: 17901–17905.

    Article  CAS  PubMed  Google Scholar 

  42. Lochhead PA, Gilley R, Cook SJ . ERK5 and its role in tumour development. Biochem Soc Trans 2012; 40: 251–256.

    Article  CAS  PubMed  Google Scholar 

  43. Drew BA, Burow ME, Beckman BS . MEK5/ERK5 pathway: the first fifteen years. Biochim Biophys Acta 2012; 1825: 37–48.

    CAS  PubMed  Google Scholar 

  44. Medina PP, Castillo SD, Blanco S, Sanz-Garcia M, Largo C, Alvarez S et al. The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer. Hum Mol Genet 2009; 18: 1343–1352.

    Article  CAS  PubMed  Google Scholar 

  45. Liu P, Ramachandran S, Ali Seyed M, Scharer CD, Laycock N, Dalton WB et al. Sex-determining region Y box 4 is a transforming oncogene in human prostate cancer cells. Cancer Res 2006; 66: 4011–4019.

    Article  CAS  PubMed  Google Scholar 

  46. Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S, Verhaak RG et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 2009; 41: 1238–1242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gustavsson E, Sernbo S, Andersson E, Brennan DJ, Dictor M, Jerkeman M et al. SOX11 expression correlates to promoter methylation and regulates tumor growth in hematopoietic malignancies. Mol Cancer 2010; 9: 187.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D et al. COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Res 2011; 39: Database issue D945–D950.

    Article  CAS  PubMed  Google Scholar 

  49. Harada T, Chelala C, Bhakta V, Chaplin T, Caulee K, Baril P et al. Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays. Oncogene 2008; 27: 1951–1960.

    Article  CAS  PubMed  Google Scholar 

  50. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer discov 2012; 2: 401–404.

    Article  PubMed  Google Scholar 

  51. Yan HT, Shinka T, Sato Y, Yang XJ, Chen G, Sakamoto K et al. Overexpression of SOX15 inhibits proliferation of NT2/D1 cells derived from a testicular embryonal cell carcinoma. Mol Cells 2007; 24: 323–328.

    CAS  PubMed  Google Scholar 

  52. Beranger F, Mejean C, Moniot B, Berta P, Vandromme M . Muscle differentiation is antagonized by SOX15, a new member of the SOX protein family. J Biol Chem 2000; 275: 16103–16109.

    Article  CAS  PubMed  Google Scholar 

  53. Lee HJ, Goring W, Ochs M, Muhlfeld C, Steding G, Paprotta I et al. Sox15 is required for skeletal muscle regeneration. Mol Cell Biol 2004; 24: 8428–8436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Meeson AP, Shi X, Alexander MS, Williams RS, Allen RE, Jiang N et al. Sox15 and Fhl3 transcriptionally coactivate Foxk1 and regulate myogenic progenitor cells. EMBO J 2007; 26: 1902–1912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Savage J, Conley AJ, Blais A, Skerjanc IS . SOX15 and SOX7 differentially regulate the myogenic program in P19 cells. Stem Cells 2009; 27: 1231–1243.

    Article  CAS  PubMed  Google Scholar 

  56. Ito M . Function and molecular evolution of mammalian Sox15, a singleton in the SoxG group of transcription factors. Int J Biochem Cell Biol 2010; 42: 449–452.

    Article  CAS  PubMed  Google Scholar 

  57. White BD, Chien AJ, Dawson DW . Dysregulation of Wnt/beta-catenin signaling in gastrointestinal cancers. Gastroenterology 2012; 142: 219–232.

    Article  CAS  PubMed  Google Scholar 

  58. Yao H, Ashihara E, Maekawa T . Targeting the Wnt/beta-catenin signaling pathway in human cancers. Expert Opin Ther Targets 2011; 15: 873–887.

    Article  CAS  PubMed  Google Scholar 

  59. Polakis P . Drugging Wnt signalling in cancer. EMBO J 2012; 31: 2737–2746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Klarmann GJ, Decker A, Farrar WL . Epigenetic gene silencing in the Wnt pathway in breast cancer. Epigenetics 2008; 3: 59–63.

    Article  PubMed  Google Scholar 

  61. Dihlmann S, von Knebel Doeberitz M . Wnt/beta-catenin-pathway as a molecular target for future anti-cancer therapeutics. Int J Cancer 2005; 113: 515–524.

    Article  CAS  PubMed  Google Scholar 

  62. Moon RT, Kohn AD, De Ferrari GV, Kaykas A . WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 2004; 5: 691–701.

    Article  CAS  PubMed  Google Scholar 

  63. Bibikova M, Lin Z, Zhou L, Chudin E, Garcia EW, Wu B et al. High-throughput DNA methylation profiling using universal bead arrays. Genome Res 2006; 16: 383–393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ishkanian AS, Malloff CA, Watson SK, DeLeeuw RJ, Chi B, Coe BP et al. A tiling resolution DNA microarray with complete coverage of the human genome. Nat Genet 2004; 36: 299–303.

    Article  CAS  PubMed  Google Scholar 

  65. Khojasteh M, Lam WL, Ward RK, MacAulay C . A stepwise framework for the normalization of array CGH data. BMC bioinformatics 2005; 6: 274.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Coe BP, Chari R, MacAulay C, Lam WL . FACADE: a fast and sensitive algorithm for the segmentation and calling of high resolution array CGH data. Nucleic Acids Res 2010; 38: e157.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Simon R, Lam A, Li MC, Ngan M, Menenzes S, Zhao Y . Analysis of gene expression data using BRB-ArrayTools. Cancer Inform 2007; 3: 11–17.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Mak AB, Ni Z, Hewel JA, Chen GI, Zhong G, Karamboulas K et al. A lentiviral functional proteomics approach identifies chromatin remodeling complexes important for the induction of pluripotency. Mol Cel Proteomics 2010; 9: 811–823.

    Article  CAS  Google Scholar 

  69. Dull T, Zufferey R, Kelly M, Mandel RJ, Nguyen M, Trono D et al. A third-generation lentivirus vector with a conditional packaging system. J Virol 1998; 72: 8463–8471.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Thu KL, Pikor LA, Chari R, Wilson IM, Macaulay CE, English JC et al. Genetic disruption of KEAP1/CUL3 E3 ubiquitin ligase complex components is a key mechanism of NF-kappaB pathway activation in lung cancer. J Thorac Oncol 2011; 6: 1521–1529.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Lockwood WW, Thu KL, Lin L, Pikor LA, Chari R, Lam WL et al. Integrative genomics identified RFC3 as an amplified candidate oncogene in esophageal adenocarcinoma. Clin Cancer Res 2012; 18: 1936–1946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Radulovich N, Qian JY, Tsao MS . Human pancreatic duct epithelial cell model for KRAS transformation. Methods Enzymol 2008; 439: 1–13.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

KLT, NR and LAP are supported by Vanier Canada Graduate Scholarships, DDBS by University of British Columbia 4YF scholarship and WWL by a CIHR Jean-Francois Saint Denis Fellowship in Cancer Research. This work was supported by grants from the Canadian Cancer Society Research Institute (#700809), the Canadian Institutes for Health Research, PMH Foundation and Ontario Ministry of Health and Long Term Care. MST is the M Qasim Choksi Chair in Lung Cancer Translational Research.

Author information

Authors and Affiliations

  1. BC Cancer Research Centre, Vancouver, BC, Canada

    K L Thu, D D Becker-Santos, L A Pikor, A Pusic, W W Lockwood & W L Lam

  2. University Health Network and Department of Laboratory Medicine and Pathobiology, Ontario Cancer Institute, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada

    N Radulovich & M-S Tsao

Authors
  1. K L Thu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N Radulovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D D Becker-Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L A Pikor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Pusic
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W W Lockwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W L Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M-S Tsao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to W L Lam or M-S Tsao.

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

Thu, K., Radulovich, N., Becker-Santos, D. et al. SOX15 is a candidate tumor suppressor in pancreatic cancer with a potential role in Wnt/β-catenin signaling. Oncogene 33, 279–288 (2014). https://doi.org/10.1038/onc.2012.595

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.595

Keywords

This article is cited by

Search

Advanced search

Quick links