title: ESE3/EHF controls epithelial cell differentiation and its loss leads to prostate tumors with mesenchymal and stem-like features.
abstract: Cancer stem cells (CSC) play a significant role in tumor progression, disease recurrence, and treatment failure. Here, we show that the endogenously expressed ETS transcription factor ESE3/EHF controls prostate epithelial cell differentiation and stem-like potential. We found that loss of ESE3/EHF induced epithelial-to-mesenchymal transition (EMT), stem-like features, and tumor-initiating and metastatic properties in prostate epithelial cells, and reexpression of ESE3/EHF inhibited the stem-like properties and tumorigenic potential of prostate cancer cells. Mechanistically, ESE3/EHF repressed the expression of key EMT and CSC genes, including TWIST1, ZEB2, BMI1, and POU5F1. Analysis of human tissue microarrays showed that reduced ESE3/EHF expression is an early event in tumorigenesis, frequently occurring independently of other ETS gene alterations. Additional analyses linked loss of ESE3/EHF expression to a distinct group of prostate tumors with distinctive molecular and biologic characteristics, including increased expression of EMT and CSC genes. Low ESE3/EHF expression was also associated with increased biochemical recurrence of prostate cancer and reduced overall survival after prostatectomy. Collectively, our findings define a key role for ESE3/EHF in the development of a subset of prostate tumors and highlight the clinical importance of identifying molecularly defined tumor subgroups.
authors.affiliation: Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Domenico
authors.initials: D
authors.lastname: Albino
authors.forename: Nicole
authors.initials: N
authors.lastname: Longoni
authors.forename: Laura
authors.initials: L
authors.lastname: Curti
authors.forename: Maurizia
authors.initials: M
authors.lastname: Mello-Grand
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinton
authors.forename: Gianluca
authors.initials: G
authors.lastname: Civenni
authors.forename: George
authors.initials: G
authors.lastname: Thalmann
authors.forename: Gioacchino
authors.initials: G
authors.lastname: D'Ambrosio
authors.forename: Manuela
authors.initials: M
authors.lastname: Sarti
authors.forename: Fausto
authors.initials: F
authors.lastname: Sessa
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chiorino
authors.forename: Carlo V
authors.initials: CV
authors.lastname: Catapano
authors.forename: Giuseppina M
authors.initials: GM
authors.lastname: Carbone
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000166:cytology*; D058750:Epithelial-Mesenchymal Transition; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D015534:Trans-Activators / Q000032:analysis; D014157:Transcription Factors / Q000502:physiology*; D000071230:Transcriptional Regulator ERG
chemical_list: C403306:EHF protein, human; C072312:ERG protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG