Skip to main content

Advertisement

SpringerLink
Log in

Positive Expression of LSD1 and Negative Expression of E-cadherin Correlate with Metastasis and Poor Prognosis of Colon Cancer

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

The first identified lysine-specific demethylase, LSD1, plays an important role in the metastatic progression of several types of cancer.

Aims

The aim of this study was to investigate LSD1, E-cadherin, and N-cadherin expression in colon cancer specimens and their clinical significance.

Methods

The expression of LSD1, E-cadherin, and N-cadherin in colon cancer specimens was determined by immunohistochemistry, and the relationship between the expression of the respective molecules and clinicopathological characteristics was analyzed.

Results

The positive expression rates of LSD1, E-cadherin, and N-cadherin in colon cancer specimens were 66.7 % (72/108), 85.2 % (92/108), and 41.7 % (45/108), respectively. LSD1 was significantly more highly expressed in colon cancer specimens classified as high TNM stage lesions and with distant metastasis (P < 0.05). Further analysis demonstrated that LSD1 expression was positively correlated with lymph node and distant metastases (P < 0.05). However, E-cadherin expression was significantly downregulated in colon cancer specimens classified as high TNM stage lesions and with distant metastasis (P < 0.05), whereas the expression of N-cadherin did not differ significantly according to clinical and pathological characteristics (P > 0.05). Correlation analysis revealed that LSD1 expression was negatively correlated with E-cadherin expression (r s = −0.318, P = 0.001), but not evidently correlated with N-cadherin expression (r s = 0.182, P = 0.06). Colon cancer specimens with positive LSD1 expression and negative E-cadherin expression were correlated with significantly lower overall survival.

Conclusions

LSD1 showed a significantly higher expression, in contrast to the significantly lower expression of E-cadherin, in colon cancer specimens classified as high TNM stage lesions and with distant metastasis. Positive expression of LSD1 and negative expression of E-cadherin may be predictors of a worse colon cancer prognosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Cui R, Okada Y, Jang SG, et al. Common variant in 6q26-q27 is associated with distal colon cancer in an Asian population. Gut. 2011;60:799–805.

    Article  PubMed  CAS  Google Scholar 

  2. Center MM, Jemal A, Ward E. International trends in colorectal cancer incidence rates. Cancer Epidemiol Biomarkers Prev. 2009;18:1688–1694.

    Article  PubMed  Google Scholar 

  3. Center MM, Jemal A, Smith RA, et al. Worldwide variations in colorectal cancer. CA Cancer J Clin. 2009;59:366–378.

    Article  PubMed  Google Scholar 

  4. Boyer B, Vallés AM, Edme N. Induction and regulation of epithelial–mesenchymal transitions. Biochem Pharmacol. 2000;60:1091–1099.

    Article  PubMed  CAS  Google Scholar 

  5. Kang Y, Massagué J. Epithelial–mesenchymal transitions: twist in development and metastasis. Cell. 2004;118:277–279.

    Article  PubMed  CAS  Google Scholar 

  6. Hajra KM, Chen DY, Fearon ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 2002;62:1613–1618.

    PubMed  CAS  Google Scholar 

  7. Chang ZG, Wei JM, Qin CF, et al. Suppression of the epidermal growth factor receptor inhibits epithelial–mesenchymal transition in human pancreatic cancer PANC-1 cells. Dig Dis Sci. 2012;57:1181–1189.

    Article  PubMed  CAS  Google Scholar 

  8. Dai YH, Tang YP, Zhu HY, et al. ZEB2 promotes the metastasis of gastric cancer and modulates epithelial mesenchymal transition of gastric cancer cells. Dig Dis Sci. 2012;57:1253–1260.

    Article  PubMed  CAS  Google Scholar 

  9. Batlle E, Sancho E, Francí C, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2:84–89.

    Article  PubMed  CAS  Google Scholar 

  10. Lin T, Ponn A, Hu X, et al. Requirement of the histone demethylase LSD1 in Snai1-mediated transcriptional repression during epithelial-mesenchymal transition. Oncogene. 2010;29:4896–4904.

    Article  PubMed  CAS  Google Scholar 

  11. Mosammaparast N, Shi Y. Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Annu Rev Biochem. 2010;79:155–179.

    Article  PubMed  CAS  Google Scholar 

  12. Cho HS, Suzuki T, Dohmae N, et al. Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. Cancer Res. 2011;71:655–660.

    Article  PubMed  CAS  Google Scholar 

  13. Lv T, Yuan D, Miao X, et al. Over-expression of LSD1 promotes proliferation, migration and invasion in non-small cell lung cancer. PLoS ONE. 2012;7:e35065.

    Article  PubMed  CAS  Google Scholar 

  14. Compton CC, Greene FL. The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin. 2004;54:295–308.

    Article  PubMed  Google Scholar 

  15. Serce N, Gnatzy A, Steiner S, et al. Elevated expression of LSD1 (lysine-specific demethylase 1) during tumour progression from pre-invasive to invasive ductal carcinoma of the breast. BMC Clin Pathol. 2012;12:13.

    Article  PubMed  Google Scholar 

  16. Nenutil R, Smardova J, Pavlova S, et al. Discriminating functional and non-functional p53 in human tumors by p53 and MDM2 immuno-histochemistry. J Pathol. 2005;207:251–259.

    Article  PubMed  CAS  Google Scholar 

  17. Lucia MS, Miller GJ. Histopathology of malignant lesions of the penis. Urol Clin North Am. 1992;19:227–246.

    PubMed  CAS  Google Scholar 

  18. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148–1159.

    Article  PubMed  CAS  Google Scholar 

  19. Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet. 2006;7:21–33.

    Article  PubMed  CAS  Google Scholar 

  20. Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119:941–953.

    Article  PubMed  CAS  Google Scholar 

  21. Shi Y, Whetstine JR. Dynamic regulation of histone lysine methylation by demethylases. Mol Cell. 2007;25:1–14.

    Article  PubMed  CAS  Google Scholar 

  22. Mimasu S, Sengoku T, Fukuzawa S, et al. Crystal structure of histone demethylase LSD1 and tranylcypromine at 2.25 A. Biochem Biophys Res Commun. 2008;366:15–22.

    Article  PubMed  CAS  Google Scholar 

  23. Yang M, Culhane JC, Szewczuk LM, et al. Structural basis of histone demethylation by LSD1 revealed by suicide inactivation. Nat Struct Mol Biol. 2007;14:535–539.

    Article  PubMed  CAS  Google Scholar 

  24. Lee MG, Wynder C, Cooch N, et al. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature. 2005;437:432–435.

    PubMed  CAS  Google Scholar 

  25. Gatta R, Mantovani R. NF-Y substitutes H2A–H2B on active cell-cycle promoters: recruitment of CoREST-KDM1 and fine-tuning of H3 methylations. Nucleic Acids Res. 2008;36:6592–6607.

    Article  PubMed  CAS  Google Scholar 

  26. Wang Y, Zhang H, Chen Y, et al. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell. 2009;138:660–672.

    Article  PubMed  CAS  Google Scholar 

  27. Lim S, Janzer A, Becker A, et al. Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis. 2010;31:512–520.

    Article  PubMed  CAS  Google Scholar 

  28. Zhao ZK, Dong P, Gu J, et al. Overexpression of LSD1 in hepatocellular carcinoma: a latent target for the diagnosis and therapy of hepatoma. Tumour Biol. 2012. doi:10.1007/s13277-012-0525-x.

    Google Scholar 

  29. Kauffman EC, Robinson BD, Downes MJ, et al. Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer. Mol Carcinog. 2011;50:931–944.

    Article  PubMed  CAS  Google Scholar 

  30. Hayami S, Kelly JD, Cho HS, et al. Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int J Cancer. 2011;128:574–586.

    Article  PubMed  CAS  Google Scholar 

  31. Bennani-Baiti IM, Machado I, Llombart-Bosch A, et al. Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma. Hum Pathol. 2012;43:1300–1307.

    Article  PubMed  CAS  Google Scholar 

  32. Huang J, Sengupta R, Espejo AB, et al. p53 is regulated by the lysine demethylase LSD1. Nature. 2007;449:105–108.

    Article  PubMed  CAS  Google Scholar 

  33. Scoumanne A, Chen X. The lysine-specific demethylase 1 is required for cell proliferation in both p53-dependent and -independent manners. J Biol Chem. 2007;282:15471–15475.

    Article  PubMed  CAS  Google Scholar 

  34. Schulte JH, Lim S, Schramm A, et al. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res. 2009;69:2065–2071.

    Article  PubMed  CAS  Google Scholar 

  35. Ferrari-Amorotti G, Fragliasso V, Esteki R, et al. Inhibiting interactions of lysine demethylase LSD1 with Snail/Slug blocks cancer cell invasion. Cancer Res. 2012;. doi:10.1158/0008-5472.CAN-12-1739.

    PubMed  Google Scholar 

  36. Wu ZQ, Li XY, Hu CY, et al. Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression. Proc Natl Acad Sci USA. 2012;109:16654–16659.

    Article  PubMed  CAS  Google Scholar 

  37. Chen Y, Jie W, Yan W, et al. Lysine-specific histone demethylase 1 (LSD1): a potential molecular target for tumor therapy. Crit Rev Eukaryot Gene Expr. 2012;22:53–59.

    Article  PubMed  CAS  Google Scholar 

  38. Huang Y, Greene E, Murray Stewart T, et al. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc Natl Acad Sci USA. 2007;104:8023–8028.

    Article  PubMed  CAS  Google Scholar 

  39. Angst BD, Marcozzi C, Magee AI. The cadherin superfamily. J Cell Sci. 2001;114:625–626.

    PubMed  CAS  Google Scholar 

  40. Greenspon J, Li R, Xiao L, et al. Sphingosine-1-phosphate regulates the expression of adherens junction protein E-cadherin and enhances intestinal epithelial cell barrier function. Dig Dis Sci. 2011;56:1342–1353.

    Article  PubMed  CAS  Google Scholar 

  41. Hazan RB, Qiao R, Keren R, et al. Cadherin switch in tumor progression. Ann N Y Acad Sci. 2004;1014:155–163.

    Article  PubMed  CAS  Google Scholar 

  42. Castro Alves C, Rosivatz E, Schott C, et al. Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the down-regulation of E-cadherin. J Pathol. 2007;211:507–515.

    Article  PubMed  CAS  Google Scholar 

  43. Dorudi S, Hanby AM, Poulsom R, et al. Level of expression of E-cadherin mRNA in colorectal cancer correlates with clinical outcome. Br J Cancer. 1995;71:614–616.

    Article  PubMed  CAS  Google Scholar 

  44. Gravdal K, Halvorsen OJ, Haukaas SA, et al. A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res. 2007;13:7003–7011.

    Article  PubMed  CAS  Google Scholar 

  45. Hulit J, Suyama K, Chung S, et al. N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation. Cancer Res. 2007;67:3106–3116.

    Article  PubMed  CAS  Google Scholar 

  46. Paschos KA, Canovas D, Bird NC. The role of cell adhesion molecules in the progression of colorectal cancer and the development of liver metastasis. Cell Signal. 2009;21:665–674.

    Article  PubMed  CAS  Google Scholar 

  47. Hazan R, Phillips G, Qiao R, et al. Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol. 2000;148:779–790.

    Article  PubMed  CAS  Google Scholar 

  48. Christofori G. Snail1 links transcriptional control with epigenetic regulation. EMBO J. 2010;29:1787–1789.

    Article  PubMed  CAS  Google Scholar 

  49. Lin Y, Wu Y, Li J, et al. The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J. 2010;29:1803–1816.

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Guizhou Provincial People’s Hospital, Guiyang, 550002, Guizhou Province, China

    Ding Jie & Zhang Zhongmin

  2. Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, China

    Liao Guoqing, Liu Sheng & Zhang Yi

  3. Department of Pathology, Guizhou Provincial People’s Hospital, Guiyang, 550002, Guizhou Province, China

    Wen Jing

  4. Department of Pathology, Hunan Provincial Cancer Hospital, Changsha, 410013, Hunan Province, China

    Zeng Liang

Authors
  1. Ding Jie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhang Zhongmin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liao Guoqing
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liu Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhang Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wen Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zeng Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ding Jie or Liao Guoqing.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jie, D., Zhongmin, Z., Guoqing, L. et al. Positive Expression of LSD1 and Negative Expression of E-cadherin Correlate with Metastasis and Poor Prognosis of Colon Cancer. Dig Dis Sci 58, 1581–1589 (2013). https://doi.org/10.1007/s10620-012-2552-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-012-2552-2

Keywords

Search

Navigation