Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway

Abstract

The DNA-binding protein TRF2 is essential for telomere protection and chromosome stability in mammals. We show here that TRF2 expression is activated by the Wnt/b-catenin signalling pathway in human cancer and normal cells as well as in mouse intestinal tissues. Furthermore, b-catenin binds to TRF2 gene regulatory regions that are functional in a luciferase transactivating assay. Reduced b-catenin expression in cancer cells triggers a marked increase in telomere dysfunction, which can be reversed by TRF2 overexpression. We conclude that the Wnt/b-catenin signalling pathway maintains a level of TRF2 critical for telomere protection. This is expected to have an important role during development, adult stem cell function and oncogenesis.

Noncanonical Functions of Telomerase: Implications in Telomerase-Targeted Cancer Therapies

“…Wnt/b-Catenin signaling can also activate the transcription of TRF2, whereas b-catenin downregulation in cancer cells aggravates telomere dysfunction (34). These data illustrate the interaction of Wnt/b-catenin signaling with telomere stabilization pathways and further corroborate existing evidence of the cross-talk between telomerase and telomerebinding proteins with cancer-promoting signaling pathways.…”

Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells

“…In the context of cancer, Tnks inhibitors may afford a single-agent synthetic-lethal strategy for targeting cancer-initiating cells that rely on mechanisms for maintaining stem cell-like characteristics. At the same time, loss of Wnt/␤-catenin signaling invoked by short or prolonged chemical attack of Porcn spares telomeres, suggesting that previous observations linking Wnt/␤-catenin-mediated transcription to telomere regulation may not be universal (37)(38)(39) (Fig. 6B).…”

miR-155 Drives Telomere Fragility in Human Breast Cancer by Targeting TRF1

“…POT1 mutations have been linked to telomeric and chromosomal abnormalities in chronic lymphocytic leukemia (11). Wnt/b-catenin signaling was shown to drive TRF2 expression, improving telomere function in cancer cells (12). In addition, TRF2 protein levels were shown to be controlled by the p53-inducible E3 ubiquitin ligase Siah1, linking shelterin function with the p53 tumor suppressor pathway (13).…”