Role of E2Fs and mitotic regulators controlled by E2Fs in the epithelial to mesenchymal transition

Abstract

The epithelial-to-mesenchymal transition (EMT) is a complex cellular process in which epithelial cells acquire mesenchymal properties. EMT occurs in three biological settings: development, wound healing and fibrosis, and tumor progression. Despite occurring in three independent biological settings, EMT signaling shares some molecular mechanisms that allow epithelial cells to de-differentiate and acquire mesenchymal characteristics that confer cells invasive and migratory capacity to distant sites. Here we summarize the molecular mechanism that delineates EMT and we will focus on the role of E2 promoter binding factors (E2Fs) in EMT during tumor progression. Since the E2Fs are presently undruggable due to their control in numerous pivotal cellular functions and due to the lack of selectivity against individual E2Fs, we will also discuss the role of three mitotic regulators and/or mitotic kinases controlled by the E2Fs (NEK2, Mps1/TTK, and SGO1) in EMT that can be useful as drug targets. Impact statement The study of the epithelial to mesenchymal transition (EMT) is an active area of research since it is one of the early intermediates to invasion and metastasis—a state of the cancer cells that ultimately kills many cancer patients. We will present in this review that besides their canonical roles as regulators of proliferation, unregulated expression of the E2F transcription factors may contribute to cancer initiation and progression to metastasis by signaling centrosome amplification, chromosome instability, and EMT. Since our discovery that the E2F activators control centrosome amplification and mitosis in cancer cells, we have identified centrosome and mitotic regulators that may represent actionable targets against EMT and metastasis in cancer cells. This is impactful to all of the cancer patients in which the Cdk/Rb/E2F pathway is deregulated, which has been estimated to be most cancer patients with solid tumors.