Long noncoding RNA DANCR promotes invasion of prostate cancer through epigenetically silencing expression of TIMP2/3

Oncotarget. 2016 Jun 21;7(25):37868-37881. doi: 10.18632/oncotarget.9350.

Abstract

LncRNA DANCR suppresses differentiation of epithelial cells, however, its function in prostate cancer development is still unknown. In the present study, we found the expression of DANCR increases in prostate cancer tissues and cells compared to normal prostate tissues and cells, moreover, DANCR promotes invasion and migration of prostate cancer cells in vitro and metastasis of tumor xenografts in nude mice. Mechanistically, we found that TIMP2/3, which are critical metastasis inhibitor of prostate cancer, were down-regulated by DANCR synergistically with EZH2 through epigenetically silencing their promoter by chromatin immunoprecipitation assay. In addition, we further investigated whether DANCR is regulated by the differentiation-promoting androgen-androgen receptor (AR) pathway and found that DANCR expression is repressed by androgen-AR; furthermore, DANCR impedes the upregulation of TIMP2/3 and the suppression of invasion and migration by androgen-AR. On the other hand, interestingly, we found that in prostate cancer cells DANCR knockdown decreased the promotion of invasion and migration by the treatment of enzalutamide, which is an AR inhibitor. In summary, our results indicate that DANCR promotes prostate cancer invasion and metastasis through repressing the expression of TIMP2/3, and suggest that DANCR could be a potential target for preventing prostate cancer metastasis, and knockdown DANCR may lessen the potential side effect of AR inhibitor.

Keywords: DANCR; EZH2; TIMP2; TIMP3; prostate cancer.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Epigenesis, Genetic*
  • Gene Silencing
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Phenylthiohydantoin / analogs & derivatives
  • Phenylthiohydantoin / pharmacology
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / metabolism*
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Receptors, Androgen / metabolism
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism*
  • Tissue Inhibitor of Metalloproteinase-3 / metabolism*

Substances

  • AR protein, human
  • DANCR long noncoding RNA, human
  • RNA, Long Noncoding
  • Receptors, Androgen
  • TIMP2 protein, human
  • TIMP3 protein, human
  • Tissue Inhibitor of Metalloproteinase-3
  • Tissue Inhibitor of Metalloproteinase-2
  • Phenylthiohydantoin
  • enzalutamide
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein