TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway

Abstract

Ten eleven translocation (TET) enzymes catalyse the oxidative reactions of 5-methylcytosine (5mC) to promote the demethylation process. The reaction intermediate 5-hydroxymethylcytosine (5hmC) has been shown to be abundant in embryonic stem cells and tissues but strongly depleted in human cancers. Genetic mutations of TET2 gene were associated with leukaemia, whereas TET1 downregulation has been shown to promote malignancy in breast cancer. Here we report that TET1 is downregulated in colon tumours from the initial stage. TET1 silencing in primary epithelial colon cells increase their cellular proliferation while its re-expression in colon cancer cells inhibits their proliferation and the growth of tumour xenografts even at later stages. We found that TET1 binds to the promoter of the DKK gene inhibitors of the WNT signalling to maintain them hypomethylated. Downregulation of TET1 during colon cancer initiation leads to repression, by DNA methylation, the promoters of the inhibitors of the WNT pathway resulting in a constitutive activation of the WNT pathway. Thus the DNA hydroxymethylation mediated by TET1 controlling the WNT signalling is a key player of tumour growth. These results provide new insights for understanding how tumours escape cellular controls.

Regulation and Functional Significance of 5-Hydroxymethylcytosine in Cancer

“…In colorectal cancers, genes differentially hydroxymethylated between tumor and paired normal samples showed high correlation with their mRNA expression [45]. In addition, Dickkopf-related protein 3 (DDK3) was hypermethylated in colon cancer, causing to an active WNT signaling mediated tumor growth in mice [46].…”

Updates on the Molecular Genetics of Colorectal Cancer

“…TET1 suppresses tumor progression by inhibiting the WNT pathway [20]. In CRC, a decrease in TET1 messenger RNA (mRNA) has previously been observed, leading to decreased or absent levels of 5hmC [19].…”

Hydroxymethylation Influences on Intestinal Epithelial Cells in Health and Disease

“…A recent study evaluated global hydroxymethylation in colon cancer tissue compared to matched, adjacent normal tissue and demonstrated that hydroxymethylation was profoundly less in colon cancer tissue compared to normal [36]. Furthermore, Tet1, which as discussed is essential for active hydroxymethylation in intestinal epithelium cells, is decreased in colon cancer and occurs as an early event [37,38]. Additionally, in other cancers such as breast cancer, decreased Tet1 expression is associated with more aggressive malignancy and metastatic disease [11].…”