SOX4: Joining the Master Regulators of Epithelial-to-Mesenchymal Transition?

The EMT is a highly conserved multistep cellular program that, when deregulated, can adversely contribute to metastatic cancer progression, chemotherapy resistance, and tumor recurrence, thereby contributing to poor clinical outcome. ‘Master regulators’ of EMT are transcription factors that are capable of globally orchestrating the mesenchymal switch and endowing cancer cells with stem cell-like traits. SOX4 expression is elevated in a wide variety of human cancers of epithelial origin, where SOX4 expression has been associated with the loss of epithelial features and gain of mesenchymal traits, including cell migration and invasion. The epithelial-to-mesenchymal transition (EMT) is an important developmental program exploited by cancer cells to gain mesenchymal features. Transcription factors globally regulating processes during EMT are often referred as ‘master regulators’ of EMT, and include members of the Snail and ZEB transcription factor families. The SRY-related HMG box (SOX) 4 transcription factor can promote tumorigenesis by endowing cells with migratory and invasive properties, stemness, and resistance to apoptosis, thereby regulating key aspects of the EMT program. We propose here that SOX4 should also be considered as a master regulator of EMT, and we review the molecular mechanisms underlying its function. The epithelial-to-mesenchymal transition (EMT) is an important developmental program exploited by cancer cells to gain mesenchymal features. Transcription factors globally regulating processes during EMT are often referred as ‘master regulators’ of EMT, and include members of the Snail and ZEB transcription factor families. The SRY-related HMG box (SOX) 4 transcription factor can promote tumorigenesis by endowing cells with migratory and invasive properties, stemness, and resistance to apoptosis, thereby regulating key aspects of the EMT program. We propose here that SOX4 should also be considered as a master regulator of EMT, and we review the molecular mechanisms underlying its function. an enzyme that catalyzes the oxidation of multiple intracellular aldehydes to carboxylic acids, such as the conversion of retinol (vitamin A) to retinoic acid. ALDH1 is highly expressed in undifferentiated cells, including hematopoietic progenitors and intestinal crypt cells. a glycoprotein expressed at the cell surface of multiple cell types, including epithelial cells. It functions as a cell adhesion molecule and binds to distinct ligands depending on the cellular context. a cell-surface glycoprotein that functions as a receptor for various ligands, including hyaluronan, growth factors, and matrix metalloproteinases (MMPs). Activation of downstream signal transduction regulates several physiological processes including cell growth, angiogenesis, and cell survival. a complex cellular program wherein epithelial cells transdifferentiate into mesenchymal cells, acquiring migratory and invasive properties. This phenomenon is often associated with cancer progression and metastasis, but can also be observed in normal physiological settings such as wound healing and during embryogenesis. small non-coding RNA molecules. Mature miRNAs are single-stranded RNAs that comprise approximately 22 nucleotides and play a critical role in RNA silencing by binding to target sequences within the 3′ untranslated region (UTR) of the targeted mRNA. This association prevents protein synthesis and subsequently leads to mRNA degradation, and thereby can contribute to the post-transcriptional regulation of gene expression. a multiprotein complex comprising four core components: SUZ12, EED, RbAp48, and EZH2. This complex displays histone methyltransferase activity and trimethylates histone H3 on lysine 27 (H3K27me3), a modification that is associated with transcriptionally silent chromatin. can be expressed as a secreted cytokine or be present at the cell surface in a membrane-bound form. Ligand binding activates the TGF-β pathway cascade, where SMAD proteins play a crucial role. Soluble TGF-β ultimately controls a plethora of physiological processes, including cell growth, angiogenesis, and apoptosis during embryogenesis, as well as adult tissue homeostasis and pathological processes such as cancer.