title: Heparan sulfation is essential for the prevention of cellular senescence.
abstract: 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 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2), a synthetic enzyme of the sulfur donor PAPS, led to premature cell senescence in various cancer cells and in a xenograft tumor mouse model. Sodium chlorate, a metabolic inhibitor of HS sulfation also induced a cellular senescence phenotype. p53 and p21 accumulation was essential for PAPSS2-mediated cellular senescence. 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 β indicated that the augmented FGFR1/AKT signaling was specifically involved in premature senescence in a HS-dependent manner. Thus, blockade of either FGFR1 or AKT prohibited p53 and p21 accumulation and cell fate switched from cellular senescence to apoptosis. In particular, desulfation at the 2-O position in the HS chain contributed to the premature senescence via the augmented FGFR1 signaling. Taken together, we reveal, for the first time, that the proper status of HS is essential for the prevention of cellular senescence. These observations allowed us to hypothesize that the FGF/FGFR signaling system could initiate novel tumor defenses through regulating premature senescence.
authors.affiliation: Department of Biomedical Sciences, Inha University College of Medicine, Incheon, Korea.|Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, Korea.|Research Center for Radio-senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Department of Biomedical Sciences, Inha University College of Medicine, Incheon, Korea.|Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, Korea.
authors.forename: H C
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Division of Life Sciences, Korea University, Seoul, Korea.
authors.forename: D-M
authors.initials: DM
authors.lastname: Yu
authors.affiliation: Research Center for Radio-senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: B C
authors.initials: BC
authors.lastname: Kim
authors.affiliation: Research Center for Radio-senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: S M
authors.initials: SM
authors.lastname: Park
authors.affiliation: Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, Korea.|Department of Microbiology, Inha University College of Medicine, Incheon, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Division of Life Sciences, Korea University, Seoul, Korea.
authors.forename: Y-G
authors.initials: YG
authors.lastname: Ko
authors.affiliation: Department of Biomedical Sciences, Inha University College of Medicine, Incheon, Korea.|Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, Korea.
authors.forename: J-S
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006497:Heparan Sulfate / Q000502:physiology*; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009097:Multienzyme Complexes / Q000378:metabolism; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D013430:Sulfate Adenylyltransferase / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D006497:Heparan Sulfate; D009097:Multienzyme Complexes; D051057:Proto-Oncogene Proteins c-akt; D017468:Receptors, Fibroblast Growth Factor; D013430:Sulfate Adenylyltransferase; D016159:Tumor Suppressor Protein p53; C493956:CDKN1A protein, human; C495901:TP53 protein, human; C022322:PAPS synthetase