Activation of the Lin28/let-7 Axis by Loss of ESE3/EHF Promotes a Tumorigenic and Stem-like Phenotype in Prostate Cancer

Cancer Res. 2016 Jun 15;76(12):3629-43. doi: 10.1158/0008-5472.CAN-15-2665. Epub 2016 May 2.


Although cancer stem-like cells (CSC) are thought to be the most tumorigenic, metastatic, and therapy-resistant cell subpopulation within human tumors, current therapies target bulk tumor cells while tending to spare CSC. In seeking to understand mechanisms needed to acquire and maintain a CSC phenotype in prostate cancer, we investigated connections between the ETS transcription factor ESE3/EHF, the Lin28/let-7 microRNA axis, and the CSC subpopulation in this malignancy. In normal cells, we found that ESE3/EHF bound and repressed promoters for the Lin28A and Lin28B genes while activating transcription and maturation of the let-7 microRNAs. In cancer cells, reduced expression of ESE3/EHF upregulated Lin28A and Lin28B and downregulated the let-7 microRNAs. Notably, we found that deregulation of the Lin28/let-7 axis with reduced production of let-7 microRNAs was critical for cell transformation and expansion of prostate CSC. Moreover, targeting Lin28A/Lin28B in cell lines and tumor xenografts mimicked the effects of ESE3/EHF and restrained tumor-initiating and self-renewal properties of prostate CSC both in vitro and in vivo These results establish that tight control by ESE3/EHF over the Lin28/let-7 axis is a critical barrier to malignant transformation, and they also suggest new strategies to antagonize CSC in human prostate cancer for therapeutic purposes. Cancer Res; 76(12); 3629-43. ©2016 AACR.

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic
  • Humans
  • Male
  • Mice
  • MicroRNAs / physiology*
  • Neoplastic Stem Cells / pathology*
  • Prostatic Neoplasms / etiology
  • Prostatic Neoplasms / pathology*
  • RNA-Binding Proteins / physiology*
  • Transcription Factors / physiology*


  • EHF protein, human
  • Lin28A protein, human
  • MicroRNAs
  • RNA-Binding Proteins
  • Transcription Factors
  • mirnlet7 microRNA, human