Abstract
Abstract Prostate cancer (PCa) is a leading cause of cancer death worldwide. Several studies have provided evidence for the presence of self-renewing cancer stem-like cells (CSCs) in many solid tumors, including prostate cancer. Understanding the molecular mechanism leading to induction of epithelial-to-mesenchymal transition (EMT) and stemness will help to find new therapies for metastatic PCa. We have reported that the ETS factor ESE3/EHF is a tumor suppressor involved in the maintenance of the differentiation state of normal prostate epithelial cells (PrECs). Prostate epithelial cells upon knockdown of ESE3/EHF (ESE3KD PrECs) undergo transformation involving EMT, enlargement of the stem cell compartment with broad reprogramming of the transcriptome. In the process to identify the genes responsible for the activation of stemness in ESE3KD PrECs, we found a significant increase of Lin28A and Lin28B compared to control PrECs. Consistent with their crucial role in stemness maintenance, higher level of Lin28A and Lin28B were detected in the cancer stem cell compartment compared to the bulk population of adherent growing cells and in xenografts derived from the cancer stem cell-enriched population. To relate these effects directly to ESE3/EHF we searched for ETS-binding sites (EBS) in the promoters of the Lin28A and Lin28B. Computational analysis revealed putative EBS in the promoter region of both genes and chromatin immunoprecipitation confirmed the binding of ESE3/EHF to the predicted sites in PrECs and LNCaP cells. Furthermore, ESE3/EHF repressed Lin28A and Lin28B promoter activity in luciferase reporters. Transcriptional repression of Lin28A and Lin28B by ESE3/EHF was confirmed by the enrichment of repressive markers H3K9me and H3K27me in their promoters in LNCAP cells. Knockdown of Lin28A and Lin28B in ESE3KD PrECs by siRNAs reversed anchorage independent growth and in vitro prostatosphere formation. Furthermore, inhibition of Lin28A and Lin28B significantly reduced tumor initiating properties of ESE3KD PrECs in vivo. In contrast, re-expression of Lin28A and Lin28B promoted anchorage-independent growth and increased prostatosphere formation and self renewal in PrECs and LNCaP cells. Together, these data indicate that ESE3/EHF maintains in a repressed state Lin28A and Lin28B and constitutes a barrier to dedifferentiation of prostate epithelial cells. These data indicate also a role of Lin28A and Lin28B in the expansion and maintenance of the stem cell compartment in prostate cancer and underscore their validity as potential therapeutic targets. Citation Format: Domenico Albino, Gianluca Civenni, Mahnaz Nikpour, Carlo V. Catapano, Giuseppina M. R. Carbone. The ETS factor ESE3/EHF controls Lin28A and Lin28B and acts as a barrier for stemness in prostate epithelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1936. doi:10.1158/1538-7445.AM2014-1936
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