Description
TET (ten eleven translocation) family consists of TET1, TET2 and TET3 proteins, converting 5- methylcytosine to 5-hydroxymethylcytosine (5-hmC). TET family members are involved in the processes of cancer formation, inflammation, hypoxia, DNA demethylation. Hypoxia is a hallmark of solid tumors, which drives malignant progression by altering epigenetic controls. The key epigenetic change in breast tumors is DNA methylation, which promotes malignancy and increases risk of metastasis. TET1 and TET3 enzymes coordinate their functions in activation of TNFalpha-p38-MAPK signaling in response to hypoxia. In 2006, Yamanaka and colleagues discovered that mouse embryonic and adult fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by overexpressing four factors Oct3/4, Sox2, Klf4 and c-Myc (OSKM)5. TET1 modulates NANOG function by physical interaction and positively regulates the reprogramming of somatic cells. Co-expression of NANOG and TET1 increased the genome-wide levels of 5hmC. TET2 and poly (ADP-ribose) polymerase-1 (PARP-1) cooperatively finetune epigenetic modifications and upregulate expression of the pluripotency genes Nanog and Esrrb in the early stage of somatic cell reprogramming, indicating a role of TET proteins in the regulation of pluripotency genes' expression as well as their activity.
We suggest to develop small molecules, regulating TET family of proteins. In PDB databank TET2 protein structure with 5-formylcytosine is available. This structure can be used for homology-based modeling of other enzymes, members of TET family (TET1 and TET3). Then it is possible to create focused libraries of potential TET family inhibitors and perform then experimental high trhgouhput screening along with virtual screening, strcuture based drug design and in silico ADME/Tox optimization with folllowing experimental ADME/Tox evaluation. As a result we should get clinical trials candidate, regulating TET family in hypoxic tumors.
