β-catenin activates telomerase in stem cells and cancer cells.
Major finding: β-catenin activates telomerase in stem cells and cancer cells.
Mechanism: Recruitment of β-catenin to the Tert promoter by KLF4 leads to increased Tert expression.
Impact: β-catenin mutations in human cancers may increase TERT expression and telomere stabilization.
Telomeres are regions of repetitive nucleotides that protect the ends of chromosomes from degradation and shorten with each round of DNA replication. Self-renewing cells, such as stem cells and cancer cells, express telomerase, a ribonucleoprotein that extends telomere length, to allow cell division to continue indefinitely. Hoffmeyer and colleagues observed that deletion of β-catenin in murine embryonic stem (ES) cells led to a significant reduction in the expression of the gene encoding the enzymatic subunit of telomerase, Tert. β-catenin-deficient ES cells also had significantly shorter telomeres than wild-type ES cells and ES cells with constitutive β-catenin activity. β-catenin immunoprecipitated at the Tert transcriptional start site, indicating that β-catenin mediates telomere length by directly regulating Tert expression. β-catenin recruitment was dependent on the transcription factor KLF4 and led to the localization of histone methyltransferases and the acquisition of activating histone modifications at the Tert promoter. β-catenin also selectively bound to the Tert promoter in the adult stem cells of the intestinal crypt but not in the differentiated epithelial cells of the villi, which was associated with higher Tert expression in the crypt cells compared with the villi. Tert expression could be induced in the villi by conditional activation of β-catenin, providing further in vivo evidence for transcriptional regulation of Tert by β-catenin. TERT was also regulated by β-catenin in human colorectal cancer cells, and high β-catenin levels were significantly correlated with high TERT expression in colorectal cancer expression datasets. These findings suggest that mutational activation of the WNT pathway, which occurs in most human colorectal cancers and in many other malignancies, directly leads to telomerase activation to promote cellular immortalization.
Hoffmeyer K, Raggioli A, Rudloff S, Anton R, Hierholzer A, Del Valle I, et al. Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science 2012;336:1549–54.
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