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The WNT signalling pathway has a crucial role in regulating pluripotency in stem cells and its misregulation is common in cancers. Telomerase regulates telomere length, and it too has a role in stem cell biology and cancer. Here, the authors identify a direct link between the two: the WNT pathway component β-catenin can regulate the expression of the telomerase catalytic subunit TERT.

First, the authors showed that β-catenin-deficient mouse embryonic stem cells display decreased expression of Tert mRNA and TERT protein compared with wild-type cells. In β-catenin-deficient cells, reduced telomerase activity results in shorter telomeres. Conversely, stimulation of wild-type cells with WNT3A results in increased Tert expression. Using chromatin immunoprecipitation (ChIP) and luciferase reporter experiments, the authors then confirmed that Tert is a direct target of β-catenin and showed that β-catenin binds at Tert in concert with the transcription factor KLF4.

To confirm that the WNT pathway and telomerase also interact in adult stem cells, the authors analysed β-catenin binding by ChIP in the mouse intestinal crypt, which is rich in stem cells. They showed that it bound at the Tert transcription start site (TSS) in these cells and also in primary neurospheres.

An attractive hypothesis is that this interaction may be relevant to cancer cells. The authors thus developed a mouse model to analyse the β-catenin binding events in adenomatous lesions by conditionally activating a β-catenin gain-of-function allele in the villus. Here they were able to observe hyperproliferative tissue in a region of the villus in the same region as they find β-catenin binding at Tert. The authors also showed that β-catenin binds to the TSS of human Tert in two human cancer cell lines, the embryonal carcinoma cell line NTera2 and the human colorectal carcinoma cell line SW480. Furthermore, small interfering RNA knockdown of β-catenin in these cells reduced the expression levels of Tert mRNA.

The authors thus propose a model in which mutations in β-catenin in cancers result in increased telomerase activity — a potential line of investigation for therapy.