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

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.

细胞可塑性由间质上皮转化（mesenchymal to epithelial transition, MET）与其反向程序上皮间质转化（Epithelial-Mesenchymal Transition, EMT）之间的动态平衡所调控，这一过程在肿瘤转移级联反应中发挥关键作用。已知多种转录因子（transcription factors, TFs）可调控上皮间质转化（EMT），但目前间质上皮转化（MET）的具体调控机制仍未阐明。本研究揭示了两个转录因子OVOL1与OVOL2的全新功能：它们可作为人类癌症间质上皮转化的关键诱导因子。研究结果显示，OVOL家族转录因子可通过与诱导上皮间质转化的转录因子ZEB1形成调控反馈环路，并通过诱导上皮剪接调控蛋白1（Epithelial Splicing Regulatory Protein 1, ESRP1）的表达来调控信使RNA（messenger RNA, mRNA）剪接，从而实现对间质上皮转化的调控。利用小鼠前列腺肿瘤模型，本研究证实：在间质型前列腺癌细胞中过表达OVOL家族转录因子，可显著降低其肿瘤转移潜能。通过对917株癌细胞系的表达谱分析，进一步验证了OVOL家族转录因子作为间质上皮转化诱导因子的功能，提示其在癌症进程中作为上皮-间质细胞可塑性的关键调控因子发挥重要作用。