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

While 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 research. 2016 May 02 [Epub ahead of print]

Domenico Albino, Gianluca Civenni, Cecilia Dallavalle, Martina Roos, Hartmut Jahns, Laura Curti, Simona Rossi, Sandra Pinton, Gioacchino D'Ambrosio, Fausto Sessa, Jonathan Hall, Carlo V Catapano, Giuseppina M Carbone

Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research., Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research., Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research., Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences., Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences., Laboratory of Experimental Oncology, Institute of Oncology Research., Institute of Oncology Research, Oncology Institute of Southern Switzerland (IOSI)., Laboratory of Experimental Oncology, Institute of Oncology Research., IRCCS Multimedica., Pathology, Uninsubria University., Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences., 1Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research., Institute of Oncology Research, Oncology Institute of Southern Switzerland (IOSI) .

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