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Study suggests TET1 enzyme may prove important target for cancer diagnostics, treatment
28 November 2014 - 28 November 2014 – A new University of Iowa (UI) study which provided a deeper understanding of how KRAS turns off tumour suppressor genes, identifying a key enzyme, called TET1, in the process, suggests that this enzyme may be an important target for cancer diagnostics and treatment.

The findings from the study were published online this week in the journal Cell Reports.

Mutations in the KRAS gene have long been known to cause cancer. Around one third of solid tumours have KRAS mutations or mutations in the KRAS pathway. KRAS promotes cancer formation not only by driving cell growth and division, but also by turning off protective tumour suppressor genes, which normally limit uncontrolled cell growth and cause damaged cells to self-destruct.

Tumour suppressor genes are turned off, or silenced in KRAS-driven cancers, because the DNA that controls these genes' expression is modified by methylation. The UI study demonstrates that KRAS promotes this methylation-associated gene silencing by turning off the TET1 enzyme, which can remove methyl marks from DNA.

Dr. Charles Brenner, the Roy J. Carver Chair of Biochemistry in the UI Carver College of Medicine and senior author of the study, explained that study researchers found that one of the ways tumour suppressor genes become methylated when KRAS is activated is that an 'eraser' of the methyl marks, namely the enzyme TET1, is no longer expressed. As Brenner noted, this methyl eraser is normally expressed in non-malignant cells, yet when KRAS is activated, the eraser is silenced, leading to accumulation of silencing methyl marks.

Cells which have become cancerous as a result of KRAS mutation proliferate abnormally, forming colonies. Brenner and lead study author Dr. Bo-Kuan Wu, found that adding TET1 back to these cells reactivates tumour suppressor genes and is enough to decrease their abnormal proliferation. Furthermore, removing KRAS signalling from cancer cells reduces the cells' malignancy, but taking TET1 away from these cells is enough to make them cancerous again, even without KRAS.

The study results, implicating that TET1 is a significant player in the KRAS pathway, could help physicians decide which treatments are most likely to work for a patient's tumour. The study identifies the pathway within the KRAS biochemical cascade where the TET1 enzyme is silenced. Inhibitor drugs blocking this pathway are available.

Brenner says that these inhibitors work in some tumours and not in others. According to scientists in the study, the ability of an inhibitor to allow TET1 to be re-expressed may be a very strong biomarker for whether that drug will work in that tumour.

The ability to reactivate TET1 gene expression in tumour cells may also be a way to test the therapeutic potential of new compounds in development for cancer treatment.

Researchers in the study believe that activating TET1 may be a general therapeutic strategy for numerous malignancies.
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