CPEB1 orchestrates a fine-tuning of miR-145-5p tumor-suppressive activity on TWIST1 translation in prostate cancer cells.

Fatemeh Rajabi,Antonella Farsetti,Marina Pinskaya,Christian Gespach,Win-Yan Liu-Bordes,Arturo Londoño-Vallejo,Guillaume Pinna,Gueorgui Kratassiouk,Simona Nanni,Irina Groisman,Foretek Dominika

doi:10.18632/oncotarget.27806

Abstract

TWIST1 is a basic helix-loop-helix transcription factor, and one of the master Epithelial-to-Mesenchymal Transition (EMT) regulators. We show that tumor suppressor miR-145-5p controls TWIST1 expression in an immortalized prostate epithelial cell line and in a tumorigenic prostate cancer-derived cell line. Indeed, shRNA-mediated miR-145-5p silencing enhanced TWIST1 expression and induced EMT-associated malignant properties in these cells. However, we discovered that the translational inhibitory effect of miR-145-5p on TWIST1 is lost in 22Rv1, another prostate cancer cell line that intrinsically expresses high levels of the CPEB1 cytoplasmic polyadenylation element binding protein. This translational regulator typically reduces TWIST1 translation efficiency by shortening the TWIST1 mRNA polyA tail. However, our results indicate that the presence of CPEB1 also interferes with the binding of miR-145-5p to the TWIST1 mRNA 3′UTR. Mechanistically, CPEB1 binding to its first cognate site either directly hampers the access to the miR-145-5p response element or redirects the cleavage/polyadenylation machinery to an intermediate polyadenylation site, resulting in the elimination of the miR-145-5p binding site. Taken together, our data support the notion that the tumor suppressive activity of miR-145-5p on TWIST1 translation, consequently on EMT, self-renewal, and migration, depends on the CPEB1 expression status of the cancer cell. A preliminary prospective study using clinical samples suggests that reconsidering the relative status of miR-145-5p/TWIST1 and CPEB1 in the tumors of prostate cancer patients may bear prognostic value.

Highlights

Prostate cancer (PCa) is a leading cause of cancerrelated deaths in men
Depletion of miR145-5p in 22Rv1 cells was limited, TWIST1 mRNA and protein levels were not affected in this particular cell line, suggesting that miR-145-5p-dependent control of TWIST1 could depend on the cell type
We have discovered that miR-145-5p mediated control of TWIST1 in human prostate cancer cells is context-dependent, since it relies on the Cytoplasmic Polyadenylation Element Binding protein1 (CPEB1) expression level

Summary

Introduction

Prostate cancer (PCa) is a leading cause of cancerrelated deaths in men. Initial surgical or hormonal treatments are succeeded by a relatively high incidence of recurrence, often attributed to the persistence of stem cell-like cancer cells. Similar to what occurs in other carcinomas, Epithelial-toMesenchymal Transition (EMT), a process characterized by decreased expression of epithelial markers and increased mesenchymal markers, plays a critical role in prostate cancer cell invasion, metastasis, and tumor recurrence, by conferring cancer tumor cells with higher migration capacity and chemotherapy resistance [1,2,3]. The basic Helix-Loop-Helix (bHLH) transcription factor TWIST1 is one of the six transcription factors that control EMT during normal development, but that can promote EMT and tumor metastasis in cancer cells [4, 5]. Overexpression of TWIST1 has been observed in various types of cancer, including breast, prostate, gastric, pancreatic, bladder, and hepatocellular carcinoma, as well as in rhabdomyosarcoma and glioma, and is often associated with more aggressive phenotypes and acquired drug resistance, as reviewed in [6]. The same phenomenon has been observed in MCF-10ANeoT cells undergoing EMT [10]

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