Transcription Factors OVOL1 and OVOL2 Induce the Mesenchymal to Epithelial Transition in Human Cancer

TLDR

Cell plasticity governed by the balance between mesenchymal‑to‑epithelial transition (MET) and epithelial‑to‑mesenchymal transition (EMT) is essential for metastasis, yet the mechanisms driving MET remain poorly understood. This study identifies OVOL1 and OVOL2 as novel, critical inducers of MET in human cancers. In mouse prostate tumor models, ectopic expression of OVOL1/2 in mesenchymal cancer cells suppresses metastatic potential. OVOL1/2 promote MET through a feedback loop with the EMT‑inducing TF ZEB1 and by upregulating ESRP1‑mediated splicing, and their expression across 917 cancer cell lines underscores their central role in epithelial‑mesenchymal plasticity.

Abstract

Cell plasticity regulated by the balance between the mesenchymal to epithelial transition (MET) and the opposite program, EMT, is critical in the metastatic cascade. Several transcription factors (TFs) are known to regulate EMT, though the mechanisms of MET remain unclear. We demonstrate a novel function of two TFs, OVOL1 and OVOL2, as critical inducers of MET in human cancers. Our findings indicate that the OVOL-TFs control MET through a regulatory feedback loop with EMT-inducing TF ZEB1, and the regulation of mRNA splicing by inducing Epithelial Splicing Regulatory Protein 1 (ESRP1). Using mouse prostate tumor models we show that expression of OVOL-TFs in mesenchymal prostate cancer cells attenuates their metastatic potential. The role of OVOL-TFs as inducers of MET is further supported by expression analyses in 917 cancer cell lines, suggesting their role as crucial regulators of epithelial-mesenchymal cell plasticity in cancer.