Abstract 5019: Loss of the ETS transcription factor ESE3 induces epithelial-mesenchimal transition and generates cells with stem cell-like properties

Abstract

Abstract ETS transcription factors have emerged as important elements in the pathogenesis of prostate cancer. Most ETS factors promote cell proliferation, survival and transformation, while few others act as tumor suppressors. We have recently reported that the epithelial-specific ETS factor ESE3 is frequently down-regulated in prostate cancer, affects negatively cell proliferation and survival, and acts as tumor suppressor in prostate epithelial cells. ESE3 signatures extracted from prostate cancer clinical samples indicated a broad dedifferentiation program. Thus, we hypothesized that ESE3 maintains the differentiation state of prostate epithelial cells and that its loss leads to cell transformation. In this study, we report that stable knock-down of ESE3 in immortalized human prostate epithelial LHS cells (LHS-ESE3kd) resulted in the induction of epithelial-mesenchymal transition (EMT) with the acquisition of a fibroblast-like appearance. Concomitantly, LHS-ESE3kd cells acquired also ability to grow in anchorage-independent conditions in soft-agar and to form prostatosheres in sphere-forming assays. Expression of various stem-cell markers was also increased in LHS-ESE3kd compared to LHS cells. In a panel of prostate cell lines the ability to form prostatospheres was inversely correlated with ESE3 expression level, providing further support to the idea that the gene is an important regulator of the stem cell compartment. Consistently, re-expression of ESE3 in DU145 cells, which do not express ESE3, induced morphological changes consistent with a mesenchymal-epithelial transition, reduced the ability of the cells to migrate and to form prostatospheres. Cancer stem cells are reportedly to be drug resistant and drugs like taxol can select for drug-resistant cells with stem cell properties. We observed that resistance to taxol was inversely correlated with ESE3 expression in prostate cell lines. Furthermore, treatment of LHS-ESE3kd cells with taxol increased sphere formation, consistent with an enlargement of the stem-cell compartment by the ESE3 knock-down and increased selection by the drug. Collectively, these findings implicate that ESE3 controls the differentiation state and stem cell properties of prostate epithelial cells and that loss of ESE3 can be an important event in prostate tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5019.