Study Finds TET1 Linked To Early Events In Colon Cancer Development

Study Finds TET1 Linked To Early Events In Colon Cancer Development

shutterstock_185846456Results of a recent study titled “TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway” and published in the Oncogene journal, have shown that TET1 loss in colon cancer is an early event that favors tumor cell proliferation.

DNA methylation has an essential role in remodeling chromatin structure during development and tissue differentiation, and abnormalities in DNA methylation establishment can lead to genetic diseases and ultimately cancer.

5-Hydroxymethylcytosine (5hmC) has been identified as an epigenetic mutation catalyzed by the ten eleven translocation (TET) proteins that ultimately leads to DNA demethylation.

Even though 5hmC has been shown to disappear in different types of cancer, however, its biological relevance is still not known.

Since downregulation of TET1 has been linked to cancer invasion and metastasis, the research team led by Torino University, Italy, sought to understand the molecular mechanisms behind these events.

The researchers analyzed the levels of TET1 and hydroxymethylation in colon tumours, finding that TET1 and 5hmC are strongly reduced in primary colon cancers when compared to the adjacent healthy tissue. Furthermore, the team analyzed samples from stages I to IV of colon, breast, lung and rectum primary tumors, observing that TET1, but not TET2 or TET3, was strongly down regulated in tumors since stage I, implicating this gene in early tumorigenesis events. Importantly, they demonstrated that TET1 was involved in cell proliferation through inhibition of the WNT pathway.

The results indicate that TET1 downregulation can have implications in tumor formation, since in vitro TET1 suppression in normal epithelial colon cells allowed cell cycle progression, and its expression on altered colon cells was successful in blocking proliferation.

In a pro-tumor scenario, inhibitors of the WNT pathway in colorectal cells are inactivated via DNA methylation, allowing these transformed cells to progress into a malignant phenotype. These biological events seem to occur due to the reduced TET1-dependent demethylation activity.

As the authors state in their study, “TET1 acts as an oncosuppressor, because it has a central role in the epigenetic control of colon cancer growth. TET1 reactivation, although challenging, can represent a novel therapeutic approach in cancer”.

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