Regulation of 5-hydroxymethylcytosine by TET2 contributes to Squamous Cell Carcinoma tumorigenesis

DNA methylation is a key regulatory event controlling a variety of physiological processes and can have dramatic effects on gene transcription. Methylated Cytosine (5mC) can be oxidized by the TET family of enzymes to 5-hydroxymethylcytosine (5-hmC), a key intermediate in the de-methylation cycle, and 5-hmC levels are reduced in malignancies such as AML and melanoma. We constructed a tissue microarray of human cutaneous Squamous Cell Carcinoma (SCC) tumors and found a global reduction in 5-hmC levels compared to adjacent skin. Using a murine K14-CreER system, we have found that loss of Tet2 promotes carcinogen-induced SCC and cooperates with loss of Tp53 to drive spontaneous SCC tumors in epithelial tissues. Analysis of changes in 5-hmC and gene expression following loss of Tet2 in the epidermis revealed focal alterations in 5-hmC levels and an increase in Hair Follicle Transient Amplifying Cell (HF-TAC) genes along with a reduction in epidermal differentiation genes. These results demonstrate a role for Tet2 in epidermal lineage specification, consistent with reported roles for Tet enzymes in controlling lineage commitment in hematopoietic stem cells and ES cells and establish Tet2 as a bone fide tumor suppressor in SCC.