TET enzymes and key signalling pathways: Crosstalk in embryonic development and cancer

Abstract

TET enzymes are responsible for catalyzing the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), during the process of active DNA demethylation. These enzymes are differentially expressed in several tissues during development and can regulate several conserved signaling pathways, such as Wingless (WNT), Notch, Sonic Hedgehog (SHH) and Transforming Growth Factor Beta (TGF-β). Low expression of TET genes and the consequent reduction of 5hmC levels have been commonly reported in tumors of different origins and, in most cases, associated with poor prognosis. On this basis, we aimed to compile information about the canonical action of TET enzymes on the above signaling pathways during development, as well as the alterations characterized in different cancer cells. The presence of TETs is fundamental for normal embryonic development and their deletion in animal models has shown to delay cell differentiation and result in dysregulated expression of genes involved in signaling pathways. Consequently, the absence of TETs results in central nervous system defects and retinal deformity. In cancer, low expression of TETs induces activation of the WNT, TGF-β and NOTCH pathways, either directly or indirectly. Depletion in Tet activity inhibits tumorigenic processes, such as cell proliferation and epithelial-mesenchymal transition (EMT). The prospect of TET pharmacological or molecular manipulation might have global effects that should be considered for future therapeutic intervention. *Correspondence to: Karina Bezerra Salomão, Department of Pediatrics, Ribeirão Preto School of Medicine, University of São Paulo – USP, Avenida Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil, Tel: +55 16 3602 2651, E-mail: karina_slm@hotmail.com