Activation of the Lin28/let7 axis by loss of ESE3/EHF promotes a tumorigenic and stem-like phenotype in prostate cancer: Beyond the Abstract

From bench to bedside: strategies to target the prostate cancer stem–like compartment

Prostate cancer is the most common malignancy and the second most frequent cause of cancer-related mortality in men in developed countries. Several studies have provided evidences of the presence of self-renewing tumor-initiating stem-like cancer cells in human cancers, including prostate cancer.

Cancer stem cells (CSCs) within the primary tumors represent the most tumorigenic, metastatic and therapy resistant cell subpopulation within human tumors. Current therapies target and kill preferentially proliferating, partially differentiated tumor cells that constitute the bulk of the tumor, while sparing the rare CSC population. Our knowledge of the factors governing the behavior of CSCs in prostate cancer is limited. Understanding the pathways controlling the expansion and maintenance of prostate CSCs could be an important step toward development of more effective CSC-directed strategies for treatment of prostate cancer.

A team of researchers at the Institute of Oncology Research (IOR) in Bellinzona, Switzerland led by Dr. Giuseppina Carbone in collaboration with Dr. C. Catapano (IOR) and J. Hall (ETHZ) is currently tackling this issue in prostate cancer management. One recent accomplishment of the research team was to establish a model of prostate cancer stem cell enriched xenograft that shares features with a subgroup of prostate tumors. This was obtained by knocking down a gene that plays an important role in normal prostate differentiation. They found that by ablating the ETS transcription factor ESE3/EHF the prostate epithelial cells expand the cancer stem cell compartment. 

ESE3/EHF loss induces transcriptional reprogramming and dedifferentiation in prostate epithelial cells and human tumors.

It is relevant to note that the ablation of a single gene, ESE3/EHF, turned the normal prostate epithelial cells into aggressive cancer cells. ESE3/EHF is a transcription factor highly represented in the normal prostate. EHF binds to selected regions in DNA called ETS binding domains. The gene controls myriad of targets genes and the research team is currently unwinding the identity of these targets. Intriguingly, they observed that the gene profile of the ESE3 knockdown cells shared many features with a subgroup of tumors that they defined ESE3 low by their low level of the gene ESE3/EHF. These features include epithelial mesenchymal transition (EMT) and cancer stem cell gene expression. Thus, the established model of ESE3 knockdown prostate epithelial xenografts constitutes a valuable resource to test strategies against cancer stem cells and to potentially target the ESE3 low tumors. 

Taking advantage of this approach, more recently, the research team reported in the journal Cancer Research (Albino et al. 2016) a link between the ETS factor ESE3/EHF and the Lin28/let-7 microRNA axis, an important pathway controlling stemness. Mechanistically, they found that ESE3/EHF transcriptionally represses Lin28A and Lin28B while it activates transcription and promotes maturation of let-7 microRNAs in normal cells. Reduced expression ESE3/EHF in cancer cells leads to upregulation of Lin28A and Lin28B and downregulation of let-7 microRNAs. Deregulation of the Lin28/let-7 axis is a key event promoting cell transformation and expansion of prostate CSCs. Notably, targeting Lin28A/Lin28B in cell lines and tumor xenografts mimicked the effects of ESE3/EHF and significantly restrained tumor-initiating and self-renewal properties of prostate CSCs both in vitro and in vivo. 

These data have important therapeutic implications. Targeting Lin28A and Lin28B might directly antagonize the expansion of the CSC compartment, thus preventing survival of CSCs, generation of therapy resistant clones and disease recurrence. Consistently with this notion, Lin28A and Lin28B ablation in ESE3/EHF-KD cells and cancer cell lines resulted in decreased tumorigenic, self-renewal and tumor initiating properties in vitro and in vivo.

The selectivity of Lin28-targeting therapeutics may rely on the increased expression of Lin28 proteins in the prostate CSCs compared to normal cells and bulk tumor cells as well as their role in maintaining the stem-like state of CSCs. Lin28-targeting therapeutics might deplete the CSC compartment and allow more persistent control of the tumors, prolong disease-free survival and reduce disease recurrence. 

Thus, knowing the mechanisms by which ESE3/EHF refrains stemness may help to design alternative therapeutic strategies to reverse this deadly phenotype. Furthermore, the availability of a xenograft model that mimics prostate tumor subgroups may open new possibilities to selectively target this type of tumor. It is also expected that in a near future we could devise strategies to prevent the deleterious effect of EHF inactivation and prevent tumor progression.

Written by: Giuseppina Carbone, MD 

Institute of Oncology Research (IOR), Bellinzona, Switzerland

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