Roles and Regulations of TET Enzymes in Solid Tumors

Mutations of the TET1/2/3 gene family frequently occur in cancers of the blood and have been well characterized in driving hematological carcinogenesis. Although solid tumors present a low incidence of TET1/2/3 mutations, emerging roles of deregulated TET1/2/3 functions via multimodal mechanisms are being revealed in solid malignancies. Disrupted TET1/2/3 catalytic activity promotes local and global reconstitution of the methylation landscape that contributes to solid tumor carcinogenesis. Growing evidence suggests a secondary function of TET proteins that regulates cancer-associated genes in an enzymatic-independent manner. Limited but promising clinical trials suggest patient benefit from treatments with a TET1/2/3 coactivator in liquid cancers. Therapeutic regulation of TET1/2/3 may be an effective mechanism for re-establishing a nontumorigenic methylation landscape in not only hematological malignancies but solid cancers as well. The mechanisms governing the methylome profile of tumor suppressors and oncogenes have expanded with the discovery of oxidized states of 5-methylcytosine (5mC). Ten-eleven translocation (TET) enzymes are a family of dioxygenases that iteratively catalyze 5mC oxidation and promote cytosine demethylation, thereby creating a dynamic global and local methylation landscape. While the catalytic function of TET enzymes during stem cell differentiation and development have been well studied, less is known about the multifaceted roles of TET enzymes during carcinogenesis. This review outlines several tiers of TET regulation and overviews how TET deregulation promotes a cancer phenotype. Defining the tissue-specific and context-dependent roles of TET enzymes will deepen our understanding of the epigenetic perturbations that promote or inhibit carcinogenesis. The mechanisms governing the methylome profile of tumor suppressors and oncogenes have expanded with the discovery of oxidized states of 5-methylcytosine (5mC). Ten-eleven translocation (TET) enzymes are a family of dioxygenases that iteratively catalyze 5mC oxidation and promote cytosine demethylation, thereby creating a dynamic global and local methylation landscape. While the catalytic function of TET enzymes during stem cell differentiation and development have been well studied, less is known about the multifaceted roles of TET enzymes during carcinogenesis. This review outlines several tiers of TET regulation and overviews how TET deregulation promotes a cancer phenotype. Defining the tissue-specific and context-dependent roles of TET enzymes will deepen our understanding of the epigenetic perturbations that promote or inhibit carcinogenesis. deaminates cytosine to uracil to create a point mutation of C/G into U/G. DNA repair process for single-stranded DNA breaks or a damaged nucleotide; initiated by DNA glycosylases. regions of DNA with a high frequency of cytosine then guanine dinucleotides in 5′ to 3′ direction. CpG islands are common sites of DNA methylation. a cellular process in epithelial cells that represses epithelial properties then promotes mesenchymal characteristics and phenotypes. EMT promotes an aggressive and invasive oncogenic phenotype. somatic mutations that do not serve a functional role in promoting a tumor-associated phenotype. excises thymine from mismatched G/T base pairs. TDG is an important member of the BER pathway. protein that interacts with a transcription factor to enhance/suppress target gene transcription, respectively.