An emerging role for class I bHLH E2-2 proteins in EMT regulation and tumor progression.

EMT is a complex process whereby cells lose cell-cell interactions and other epithelial properties whilst acquiring a migratory and mesenchymal phenotype. EMT is presently recognized as an important even for tumor invasion and metastasis. Functional E-cadherin loss is a hallmark of EMT and required for tumor invasion in the majority of carcinomas. Transcriptional downregulation is one of the major mechanisms for E-cadherin suppression in carcinomas. In the last decade several E-cadherin repressors, belonging to different transcriptional families, have been identified that, importantly, also act as potent EMT inducers. One of the last additions to EMT regulators are the class I bHLH factors E2-2 (also known as TCF4). However, the hierarchical and functional interrelations between the different EMT inducers are still poorly understood. Here, we comment on the new and so far unrecognized function of E2-2 factors in EMT and discuss on the potential interactions among various EMT inducers. Emerging evidence supporting the participation of TCF4 in human malignancies is also discussed. Thus, increasing understanding of EMT and its regulators is providing meaningful insights into the present knowledge on tumor progression.