Hypermethylation of NDN promotes cell proliferation by activating the Wnt signaling pathway in colorectal cancer

Oncotarget. 2017 Jul 11;8(28):46191-46203. doi: 10.18632/oncotarget.17580.

Abstract

The progression of CRC is a multistep process involving several genetic changes or epigenetic modifications. NDN is a member of the MAGE family, encoding a protein that generally suppresses cell proliferation and acting as a transcriptional repressor. Immunohistochemical staining revealed that the expression of NDN was significantly down-regulated in CRC tissues compared with normal tissues and the down-regulation of NDN in CRC could reflect the hypermethylation of the NDN promoter. Treatment of the CRC cell line SW480 with the demethylating agent 5-Aza-CdR restored the NDN expression level. The down-regulation of NDN was closely related to poor differentiation, advanced TNM stage and poor prognosis of CRC. The inhibition of NDN promoted CRC cell proliferation by enriching cells in the S phase. Furthermore, we observed that NDN binds to the GN box in the promoter of LRP6 to attenuate LRP6 transcription and inhibit the Wnt signaling pathway in CRC. In conclusion, our study revealed that the hypermethylation of NDN promotes cell proliferation by activating the Wnt signaling pathway through directly increasing the transcription of LRP6 in CRC. These findings might provide a new theoretical basis for the pathogenesis of CRC and facilitate the development of new therapeutic strategies against CRC.

Keywords: LRP6; NDN; Wnt signaling pathway; colorectal cancer; proliferation.

MeSH terms

  • Animals
  • Azacitidine / pharmacology
  • Carcinogenesis
  • Cell Movement
  • Cell Proliferation
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA Methylation
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Neoplasm Staging
  • RNA, Small Interfering / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Wnt Signaling Pathway
  • Xenograft Model Antitumor Assays

Substances

  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • NDN protein, human
  • RNA, Small Interfering
  • Tumor Suppressor Proteins
  • Azacitidine