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The ETS factor ESE3/EHF represses IL-6 preventing STAT3 activation and expansion of the prostate cancer stem-like

Domenico Albino1,2, Gianluca Civenni1,2, Simona Rossi1,2

  • 1Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.

Oncotarget
|October 13, 2016
PubMed

Insights

Loss of ESE3/EHF in prostate cancer promotes tumor growth by activating Interleukin-6 (IL-6). Targeting the IL-6/JAK/STAT3 pathway may treat aggressive prostate tumors lacking ESE3/EHF.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Metastatic prostate cancer is a significant clinical challenge due to frequent relapse and treatment resistance.
  • Understanding prostate cancer progression pathways is crucial for disease prevention.
  • The ETS transcription factor ESE3/EHF is vital for prostate epithelial cell differentiation; its loss promotes transformation and stem-like properties.

Purpose of the Study:

  • To investigate the role of ESE3/EHF in prostate cancer progression.
  • To identify downstream targets of ESE3/EHF involved in prostate cancer development.
  • To explore the therapeutic potential of targeting the identified pathway in prostate tumors.

Main Methods:

  • Prostate epithelial cell culture and manipulation of ESE3/EHF expression.
  • Identification of IL-6 as a direct target of ESE3/EHF using chromatin immunoprecipitation.
  • In vitro and in vivo assays to assess the effects of IL-6 and JAK inhibitors on cancer cell phenotypes and tumor growth.
  • Analysis of human prostate tumor samples for ESE3/EHF, IL-6, and STAT3 expression.

Main Results:

  • Loss of ESE3/EHF activates IL-6, promoting epithelial-to-mesenchymal transition and stem-like properties in prostate cells.
  • IL-6 stimulation induces malignant phenotypes and STAT3 activation, while IL-6 inhibition reverses these effects.
  • Human prostate tumors with low ESE3/EHF and high IL-6 show activated STAT3 and markers of metastasis.
  • JAK inhibitor treatment targeting IL-6/STAT3 signaling suppressed cancer stem cell growth and self-renewal.

Conclusions:

  • ESE3/EHF loss activates the IL-6/JAK/STAT3 pathway, driving prostate cancer progression and metastasis.
  • Targeting the IL-6/JAK/STAT3 axis is a promising therapeutic strategy for ESE3/EHF-deficient prostate tumors.
  • This study reveals a novel regulatory axis in prostate cancer pathogenesis.
Keywords:
ESE3/EHFETS transcription factorIL-6cancer stem cellsprostate cancer

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