Heparan Sulfation is Essential for the Prevention of Cellular Senescence

초록

Cellular senescence is considered as an important tumor-suppressive mechanism. Here, we demonstrated that heparan sulfate (HS) prevents cellular senescence by fine-tuning of the fibroblast growth factor receptor (FGFR) signaling pathway. We found that depletion of PAPSS2 led to premature cell senescence in various cancer cells and in a xenograft tumor mouse model. Such senescence phenotypes were closely correlated with cell surface HS levels in both cancer cells and human diploid fibroblasts. The determination of the activation of receptors such as FGFR1, Met, and Insulin growth factor 1 receptor (IGF1R)β indicated that the augmented and sustained FGFR1/AKT signaling was specifically involved in premature senescence in a HS-dependent manner. In particular, desulfation at the 2-O position in the HS chain contributed to the premature senescence via the augmented and sustained FGFR1 signaling. Taken together, we reveal, for the first time, that the proper status of heparan sulfation is essential for the prevention of cellular senescence. These observations allowed us to determine how FGF signaling is tumor–suppressive in some contexts and to hypothesize that the FGF2/FGFR1 signaling system could initiate novel tumor defenses through regulating premature senescence.