Interleukin-6 induces neuroendocrine differentiation (NED) through suppression of RE-1 silencing transcription factor (REST)

Prostate. 2014 Aug;74(11):1086-94. doi: 10.1002/pros.22819. Epub 2014 May 12.


Background: Paracrine interleukin-6 (IL-6) can mediate neuroendocrine (NE) features, including the acquisition of a neurite-like phenotype and growth arrest in prostate cancer cells. However, little is known about the mechanisms underlying neuroendocrine differentiation induced by IL-6.

Methods: Immunoblotting was performed to determine the status of RE1-silencing transcription factor (REST) and of neuroendocrine markers such as Neuron-specific Enolase (NSE), chromogranin A and synaptophysin in LNCaP cells treated with IL-6. To further study the impact of REST-mediated repression on neuroendocrine differentiation (NED) in LNCaP cells, either wild-type REST or a dominant-positive form of REST, REST-VP16, in which both repressor domains of REST were replaced with the activation domain of the herpes simplex virus protein VP16, was introduced into LNCaP cells.

Results: In this study, we show that REST is suppressed in IL-6-induced neuroendocrine differentiation in LNCaP cells. Overexpression of exogenous REST abrogated IL-6-induced NED in prostate cancer cells. Expression of the recombinant REST-VP16 fusion protein activated REST target genes and other neuronal differentiation genes and produced neuronal physiological properties. In addition, REST protein turnover was accelerated in IL-6 induced NE differentiated LNCaP cells via the ubiquitin-proteasome pathway, accompanied by a decrease in the expression of the deubiquitylase HAUSP, indicating that pathway(s) priming REST degradation may be involved in IL-6 induced NE differentiation.

Conclusions: These results demonstrate that REST functions as a major switch of IL-6 induced neuroendocrine differentiation in LNCaP cells.

Keywords: REST; interleukin-6; neuroendocrine; prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biomarkers, Tumor / metabolism
  • Cell Differentiation / drug effects*
  • Cell Line, Tumor
  • Chromogranin A / metabolism
  • Down-Regulation
  • Humans
  • Interleukin-6 / pharmacology*
  • Male
  • Neuroendocrine Tumors / metabolism*
  • Neuroendocrine Tumors / pathology*
  • Phenotype
  • Phosphopyruvate Hydratase / metabolism
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • Proteasome Endopeptidase Complex / metabolism
  • Repressor Proteins / metabolism*
  • Signal Transduction / drug effects
  • Synaptophysin / metabolism
  • Ubiquitin / metabolism


  • Biomarkers, Tumor
  • Chromogranin A
  • Interleukin-6
  • RE1-silencing transcription factor
  • Repressor Proteins
  • Synaptophysin
  • Ubiquitin
  • Proteasome Endopeptidase Complex
  • Phosphopyruvate Hydratase