Transforming growth factor-β inhibits telomerase through SMAD3 and E2F transcription factors

Cancer arises from multiple genetic changes within the cell, among which constitutive telomerase activity and attainment of immortality are central. Expression of hTERT, the protein component of telomerase, is increased in most cancer cells. Transforming growth factor-β (TGFβ), a potent tumor suppressor, has been reported to regulate hTERT expression. We found that TGFβ represses hTERT expression in normal and cancer cells and that this effect is mediated through Smad3 but also requires Erk1/2, p38 kinase and histone deacetylase activity. Furthermore, we identified four critical E2F transcription factor binding sites within the hTERT gene promoter that confer the TGFβ response. Finally, using the E2F-1 knockout model, we showed that loss of E2F-1 abolishes TGFβ inhibition of telomerase expression. These findings highlight the prominent role of TGFβ in regulating telomerase expression and identify Smad3 and E2F-1 as critical mediators of TGFβ effects in both normal and cancer cells.